Skip to main content
SpringerLink
Log in

Normalizing the Tumor Microenvironment for Radiosensitization

  • Chapter
  • First Online:
Molecular Targeted Radiosensitizers

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Radiation is used in various cancer treatment regimens. However, hypoxia—a hallmark of the tumor microenvironment (TME)—drives disease progression and limits response to radiation, chemo-, immuno-, and targeted therapies. Hypoxia is a prognostic biomarker of worse outcome in most types of solid tumors. Combinations of radiation therapy and molecular targeted radiosensitizers are limited by hypoxia through multiple mechanisms. Thus, targeting the tumor microenvironment to ameliorate hypoxia is a promising strategy for cancer treatment broadly and radiosensitization specifically. Key processes that cause hypoxia are dysregulated angiogenesis and desmoplasia, which induce formation of tumor vessels that are abnormal in structure and function thereby reducing vessels’ efficiency in delivering oxygen, other nutrients, immune cells, and drugs. Judiciously inhibiting angiogenesis and desmoplasia normalizes the tumor microenvironment towards alleviating hypoxia and reversing treatment resistance. By increasing oxygen, drug, and anti-tumor immune-cell accumulation and distribution within tumors and their metastases, TME normalization could be a beneficial component of radiation regimens for many patients. We describe opportunities to combine molecular targeted and other radiosensitizers to improve outcomes in cancer patients. We also outline challenges to the preclinical development and clinical translation of these combinations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aicher A, Rentsch M, Sasaki K, Ellwart JW, Fandrich F, Siebert R, Cooke JP, Dimmeler S, Heeschen C (2007) Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res 100(4):581–589. https://doi.org/10.1161/01.RES.0000259562.63718.35

    Article  CAS  PubMed  Google Scholar 

  • Aktar R, Dietrich A, Tillner F, Kotb S, Löck S, Willers H, Baumann M, Krause M, Bütof R (2019) Pre-clinical imaging for establishment and comparison of orthotopic non-small cell lung carcinoma: in search for models reflecting clinical scenarios. Br J Radiol 92(1095):20180539

    PubMed  Google Scholar 

  • Algire GH, Chalkley HW (1945) Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants. J Natl Cancer Inst 6:73–85

    Google Scholar 

  • Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, Feyen K, Tawney J, Hanahan D, Michael IP (2017) Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med 9(385):eaak9679

    PubMed  PubMed Central  Google Scholar 

  • Arvanitis CD, Ferraro GB, Jain RK (2020) The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat Rev Cancer 20:26–41

    CAS  PubMed  Google Scholar 

  • Baine MK, Turcu G, Zito CR, Adeniran AJ, Camp RL, Chen L, Kluger HM, Jilaveanu LB (2015) Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens. Oncotarget 6(28):24990–25002

    PubMed  PubMed Central  Google Scholar 

  • Baish JW, Stylianopoulos T, Lanning RM, Kamoun WS, Fukumura D, Munn LL, Jain RK (2011) Scaling rules for diffusive drug delivery in tumor and normal tissues. Proc Natl Acad Sci U S A 108(5):1799–1803. https://doi.org/10.1073/pnas.1018154108

  • Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163(5):1801–1815

    PubMed  PubMed Central  Google Scholar 

  • Batchelor TT, Gerstner ER, Emblem KD, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK (2013) Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A 110(47):19059–19064

    Google Scholar 

  • Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95. https://doi.org/10.1016/j.ccr.2006.11.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonvalot S, Rutkowski PL, Thariat J, Carrère S, Ducassou A, Sunyach M-P, Agoston P, Hong A, Mervoyer A, Rastrelli M (2019) NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act. In. Sarc): a multicentre, phase 2–3, randomised, controlled trial. Lancet Oncol 20(8):1148–1159

    CAS  PubMed  Google Scholar 

  • Bristow RG, Alexander B, Baumann M, Bratman SV, Brown JM, Camphausen K, Choyke P, Citrin D, Contessa JN, Dicker A (2018) Combining precision radiotherapy with molecular targeting and immunomodulatory agents: a guideline by the American Society for Radiation Oncology. Lancet Oncol 19(5):e240–e251

    PubMed  Google Scholar 

  • Bussink J, Kaanders JHA, Rijken PFJ, Raleigh JA, Van der Kogel AJ (2000) Changes in blood perfusion and hypoxia after irradiation of a human squamous cell carcinoma xenograft tumor line. Radiat Res 153(4):398–404

    CAS  PubMed  Google Scholar 

  • Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, Canese R, Jachetti E, Rossetti M (2012) Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 72(11):2746–2756

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692):485–490

    CAS  PubMed  Google Scholar 

  • Carmeliet P, Jain RK (2011a) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307. https://doi.org/10.1038/nature10144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carmeliet P, Jain RK (2011b) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10(6):417–427. https://doi.org/10.1038/nrd3455

    Article  CAS  PubMed  Google Scholar 

  • Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD (2018) TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 9(1):4692

    PubMed  PubMed Central  Google Scholar 

  • Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL (2000) Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 97(26):14608–14613

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chauhan VP, Chen IX, Tong RT, Ng MR, Martin JD, Naxerova K, Wu MW, Huang P, Boucher Y, Kohane DS, Langer R, Jain RK (2019) Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc Natl Acad Sci U S A 116(22):10674–10680. https://doi.org/10.1073/pnas.1819889116/

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chauhan VP, Jain RK (2013) Strategies for advancing cancer nanomedicine. Nat Mater 12(11):958–962. https://doi.org/10.1038/nmat3792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popovic Z, Huang P, Bawendi MG, Boucher Y, Jain RK (2013) Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4:2516. https://doi.org/10.1038/ncomms3516

    Article  CAS  PubMed  Google Scholar 

  • Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK (2011) Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu Rev Chem Biomol Eng 2:281–298. https://doi.org/10.1146/annurev-chembioeng-061010-114300

    Article  CAS  PubMed  Google Scholar 

  • Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, Bawendi MG, Fukumura D, Jain RK (2012) Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 7(6):383–388. https://doi.org/10.1038/nnano.2012.45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer–immune set point. Nature 541(7637):321–330

    CAS  PubMed  Google Scholar 

  • Chen IX, Chauhan VP, Posada J, Ng MR, Wu MW, Adstamongkonkul P, Huang P, Lindeman N, Langer R, Jain RK (2019a) Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A 116(10):4558–4566

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Q, Chen J, Yang Z, Xu J, Xu L, Liang C, Han X, Liu Z (2019b) Nanoparticle-enhanced radiotherapy to trigger robust cancer immunotherapy. Adv Mater 31(10):1802228

    Google Scholar 

  • Chen Y, Huang Y, Reiberger T, Duyverman AM, Huang P, Samuel R, Hiddingh L, Roberge S, Koppel C, Lauwers GY, Zhu AX, Jain RK, Duda DG (2014) Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice. Hepatology 59(4):1435–1447. https://doi.org/10.1002/hep.26790

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Ramjiawan RR, Reiberger T, Ng MR, Hato T, Huang Y, Ochiai H, Kitahara S, Unan EC, Reddy TP, Fan C, Huang P, Bardeesy N, Zhu AX, Jain RK, Duda DG (2015) CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61(5):1591–1602. https://doi.org/10.1002/hep.27665

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Liu L, Liang R, Luo Z, He H, Wu Z, Tian H, Zheng M, Ma Y, Cai L (2018) Bioinspired hybrid protein oxygen nanocarrier amplified photodynamic therapy for eliciting anti-tumor immunity and abscopal effect. ACS Nano 12(8):8633–8645

    CAS  PubMed  Google Scholar 

  • Clément-Colmou K, Potiron V, Pietri M, Guillonneau M, Jouglar E, Chiavassa S, Delpon G, Paris F, Supiot S (2020) Influence of radiotherapy fractionation schedule on the tumor vascular microenvironment in prostate and lung cancer models. Cancers 12(1):121

    PubMed Central  Google Scholar 

  • Coleman CN, Higgins GS, Brown JM, Baumann M, Kirsch DG, Willers H, Prasanna PG, Dewhirst MW, Bernhard EJ, Ahmed MM (2016) Improving the predictive value of preclinical studies in support of radiotherapy clinical trials. Clin Cancer Res 22(13):3138–3147

    CAS  PubMed  PubMed Central  Google Scholar 

  • Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, Sirven P, Magagna I, Fuhrmann L, Bernard C (2018) Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33(3):463–479. e410

    CAS  PubMed  Google Scholar 

  • Datta M, Coussens LM, Nishikawa H, Hodi FS, Jain RK (2019) Reprogramming the tumor microenvironment to improve immunotherapy: emerging strategies and combination therapies. Am Soc Clin Oncol Educ Book 39:165–174

    PubMed  PubMed Central  Google Scholar 

  • Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11(2):728–734

    CAS  PubMed  Google Scholar 

  • Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti–CTLA-4 antibody. Clin Cancer Res 15(17):5379–5388

    CAS  PubMed  PubMed Central  Google Scholar 

  • Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK (2011) Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A 108(7):2909–2914. https://doi.org/10.1073/pnas.1018892108

    Article  PubMed  PubMed Central  Google Scholar 

  • Duda DG, Cohen KS, Kozin SV, Perentes JY, Fukumura D, Scadden DT, Jain RK (2006) Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood 107(7):2774–2776. https://doi.org/10.1182/blood-2005-08-3210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D, Jain RK (2010) Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci U S A 107(50):21677–21682

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20(21):4368–4380

    CAS  PubMed  Google Scholar 

  • Eguchi D, Ikenaga N, Ohuchida K, Kozono S, Cui L, Fujiwara K, Fujino M, Ohtsuka T, Mizumoto K, Tanaka M (2013) Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor. J Surg Res 181(2):225–233

    CAS  PubMed  Google Scholar 

  • Emblem KE, Gerstner ER, Sorensen G, Rosen BR, Wen PY, Batchelor TT, Jain RK (2016) Matrix-depleting anti-hypertensives decompress tumor blood vessels and improve perfusion in patients with glioblastomas receiving anti-angiogenic therapy. Cancer Res 76(14 Supplement):3975–3975

    Google Scholar 

  • Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJ, Wen PY, Ivy P, Batchelor TT, Rosen BR, Jain RK, Sorensen AG (2013) Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med 19(9):1178–1183. https://doi.org/10.1038/nm.3289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ergun S, Hohn HP, Kilic N, Singer BB, Tilki D (2008) Endothelial and hematopoietic progenitor cells (EPCs and HPCs): hand in hand fate determining partners for cancer cells. Stem Cell Rev 4(3):169–177. https://doi.org/10.1007/s12015-008-9028-y

    Article  CAS  PubMed  Google Scholar 

  • Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73(5):1524–1535. https://doi.org/10.1158/0008-5472.CAN-12-2796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang L-P, Gimotty PA, Gilks CB, Lal P, Zhang L (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475(7355):226–230

    CAS  PubMed  Google Scholar 

  • Feng D, Nagy JA, Hipp J, Dvorak HF, Dvorak AM (1996) Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 183(5):1981–1986

    CAS  PubMed  Google Scholar 

  • Fernández-Sánchez ME, Barbier S, Whitehead J, Béalle G, Michel A, Latorre-Ossa H, Rey C, Fouassier L, Claperon A, Brullé L (2015) Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature 523:92–95

    Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186

    CAS  PubMed  Google Scholar 

  • Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK (2018) Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 15:325–340

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fukumura D, Salehi HA, Witwer B, Tuma RF, Melder RJ, Jain RK (1995) Tumor necrosis factor α-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain. Cancer Res 55(21):4824–4829

    CAS  PubMed  Google Scholar 

  • Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94(6):715–725

    CAS  PubMed  Google Scholar 

  • Garcia-Foncillas J, Martinez P, Lahuerta A, Cussac AL, Gonzalez MG, Sanchez Gomez RM, Alvarez I, Anton A, Illarramendi JJ, De Juan A, Galve Calvo E, Plazaola A, Morales S, Hernando B, Lao J, Boni V, Puertolas T, Sherer S, Palacios G, Lopez-Vega JM (2012) Dynamic contrast-enhanced MRI versus 18F-misonidazol-PET/CT to predict pathologic response in bevacizumab-based neoadjuvant therapy in breast cancer. J Clin Oncol 30. (suppl; abstr 10512)

    Google Scholar 

  • Gerlowski LE, Jain RK (1986) Microvascular permeability of normal and neoplastic tissues. Microvasc Res 31(3):288–305

    CAS  PubMed  Google Scholar 

  • Goel S, Duda DG, Xu L, Munn LL, Boucher Y, Fukumura D, Jain RK (2011) Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 91(3):1071–1121. https://doi.org/10.1152/physrev.00038.2010

    Article  CAS  PubMed  Google Scholar 

  • Goldman E (1907) The growth of malignant disease in man and the lower animals with special reference to the vascular system. Lancet 2:1236–1240

    Google Scholar 

  • Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456(7223):809

    CAS  PubMed  PubMed Central  Google Scholar 

  • Greenblatt M, Philippe SK (1968) Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique. J Natl Cancer Inst 41(1):111–124

    CAS  PubMed  Google Scholar 

  • Grégoire V, Hunter NR, Brock WA, Hittelman WN, Plunkett W, Milas L (1996) Improvement in the therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus fludarabine. Radiat Res 146(5):548–553

    PubMed  Google Scholar 

  • Griffon-Etienne G, Boucher Y, Brekken C, Suit HD, Jain RK (1999) Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res 59(15):3776–3782

    CAS  PubMed  Google Scholar 

  • Gullino PM (1978) Angiogenesis and oncogenesis. J Natl Cancer Inst 61(3):639–643

    CAS  PubMed  Google Scholar 

  • Hagendoorn J, Tong R, Fukumura D, Lin Q, Lobo J, Padera TP, Xu L, Kucherlapati R, Jain RK (2006) Onset of abnormal blood and lymphatic vessel function and interstitial hypertension in early stages of carcinogenesis. Cancer Res 66(7):3360–3364

    CAS  PubMed  Google Scholar 

  • Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Gröne H-J, Hämmerling GJ (2008) Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453(7193):410–414

    CAS  PubMed  Google Scholar 

  • Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF (2009) Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res 69(7):3077–3085

    CAS  PubMed  Google Scholar 

  • Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S, Jain RK, McDonald DM (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380

    CAS  PubMed  PubMed Central  Google Scholar 

  • Haslam A, Prasad V (2019) Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open 2(5):e192535–e192535

    PubMed  PubMed Central  Google Scholar 

  • Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B, Abbott R, Sethumadhavan S, Philbrook P, Ko K, Cannici R (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7(277):277ra230

    Google Scholar 

  • He C, Duan X, Guo N, Chan C, Poon C, Weichselbaum RR, Lin W (2016) Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat Commun 7:12499

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heist RS, Duda DG, Sahani DV, Ancukiewicz M, Fidias P, Sequist LV, Temel JS, Shaw AT, Pennell NA, Neal JW, Gandhi L, Lynch TJ, Engelman JA, Jain RK (2015) Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. Proc Natl Acad Sci U S A 112(5):1547–1552

    Google Scholar 

  • Helmlinger G, Netti PA, Lichtenbeld HC, Melder RJ, Jain RK (1997) Solid stress inhibits the growth of multicellular tumor spheroids. Nat Biotechnol 15(8):778–783. https://doi.org/10.1038/nbt0897-778

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Kim BY, Chan CK, Hahn SM, Weissman IL, Jiang W (2018) Improving immune–vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 18(3):195–203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC (2012) Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A 109(43):17561–17566. https://doi.org/10.1073/pnas.1215397109

    Article  PubMed  PubMed Central  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342

    CAS  PubMed  Google Scholar 

  • Ide AG, Baker NH, Warren SL (1939) Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transplant ear chamber. Am J Radiol 42:891–899

    Google Scholar 

  • Isner JM (2002) Myocardial gene therapy. Nature 415:234

    CAS  PubMed  Google Scholar 

  • Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48(10):2641–2658

    CAS  PubMed  Google Scholar 

  • Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7(9):987–989. https://doi.org/10.1038/nm0901-987

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9(6):685–693. https://doi.org/10.1038/nm0603-685

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. https://doi.org/10.1126/science.1104819

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2008) Taming vessels to treat cancer. Sci Am 298(1):56–63

    PubMed  Google Scholar 

  • Jain RK (2013) Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol 31(17):2205–2218

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26(5):605–622. https://doi.org/10.1016/j.ccell.2014.10.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain RK, Carmeliet PF (2001) Vessels of death or life. Sci Am 285(6):38–45

    CAS  PubMed  Google Scholar 

  • Jain RK, Martin JD, Stylianopoulos T (2014) The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng 16:321–346. https://doi.org/10.1146/annurev-bioeng-071813-105259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain RK, Munn LL, Fukumura D (2002) Dissecting tumour pathophysiology using intravital microscopy. Nat Rev Cancer 2(4):266–276. https://doi.org/10.1038/nrc778

    Article  CAS  PubMed  Google Scholar 

  • Jain RK, Schlenger K, Hockel M, Yuan F (1997) Quantitative angiogenesis assays: progress and problems. Nat Med 3(11):1203–1208

    CAS  PubMed  Google Scholar 

  • Jain RK, Stylianopoulos T (2010) Delivering nanomedicine to solid tumors. Nat Rev Clin Oncol 7(11):653–664

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jayson GC, Kerbel R, Ellis LM, Harris AL (2016) Antiangiogenic therapy in oncology: current status and future directions. Lancet 388(10043):518–529. https://doi.org/10.1016/S0140-6736(15)01088-0

    Article  CAS  PubMed  Google Scholar 

  • Jin J, Hu C, Xiao Y, Zhang H, Ellsworth S, Schild S, Bogart J, Dobelbower M, Kavadi V, Narayan S (2017) Higher radiation dose to immune system is correlated with poorer survival in patients with stage III non-small cell lung cancer: a secondary study of a phase 3 cooperative group trial (NRG Oncology RTOG 0617). Int J Radiat Oncol Biol Phys 99(2):S151–S152

    Google Scholar 

  • Kamoun WS, Ley CD, Farrar CT, Duyverman AM, Lahdenranta J, Lacorre DA, Batchelor TT, di Tomaso E, Duda DG, Munn LL, Fukumura D, Sorensen AG, Jain RK (2009) Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 27(15):2542–2552

    Google Scholar 

  • Kirsch DG, Diehn M, Kesarwala AH, Maity A, Morgan MA, Schwarz JK, Bristow R, Demaria S, Eke I, Griffin RJ (2017) The future of radiobiology. J Natl Cancer Inst 110(4):329–340

    PubMed Central  Google Scholar 

  • Ko EC, Raben D, Formenti SC (2018) The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer. Clin Cancer Res 24(23):5792–5806

    CAS  PubMed  Google Scholar 

  • Kozin SV, Duda DG, Munn LL, Jain RK (2011) Is vasculogenesis crucial for the regrowth of irradiated tumours? Nat Rev Cancer 11(7):532. https://doi.org/10.1038/nrc2007-c1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozin SV, Duda DG, Munn LL, Jain RK (2012) Neovascularization after irradiation: what is the source of newly formed vessels in recurring tumors? J Natl Cancer Inst 104(12):899–905. https://doi.org/10.1093/jnci/djs239

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuczek DE, Larsen AMH, Thorseth M-L, Carretta M, Kalvisa A, Siersbæk MS, Simões AMC, Roslind A, Engelholm LH, Noessner E (2019) Collagen density regulates the activity of tumor-infiltrating T cells. J Immunother Cancer 7(1):68

    PubMed  PubMed Central  Google Scholar 

  • Kulkarni A, Rao P, Natarajan S, Goldman A, Sabbisetti VS, Khater Y, Korimerla N, Chandrasekar V, Mashelkar RA, Sengupta S (2016) Reporter nanoparticle that monitors its anticancer efficacy in real time. Proc Natl Acad Sci U S A 113(15):E2104–E2113

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee DC, Sohn HA, Park Z-Y, Oh S, Kang YK, Lee K-m, Kang M, Jang YJ, Yang S-J, Hong YK (2015) A lactate-induced response to hypoxia. Cell 161(3):595–609

    CAS  PubMed  Google Scholar 

  • Lee H, Shields AF, Siegel BA, Miller KD, Krop I, Ma CX, LoRusso PM, Munster PN, Campbell K, Gaddy DF (2017) 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin Cancer Res 23(15):4190–4202

    CAS  PubMed  PubMed Central  Google Scholar 

  • Less JR, Posner MC, Skalak TC, Wolmark N, Jain RK (1997) Geometric resistance and microvascular network architecture of human colorectal carcinoma. Microcirculation 4(1):25–33

    CAS  PubMed  Google Scholar 

  • Less JR, Skalak TC, Sevick EM, Jain RK (1991) Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions. Cancer Res 51(1):265–273

    CAS  PubMed  Google Scholar 

  • Levin VA, Chan J, Datta M, Yee JL, Jain RK (2017) Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. J Neuro-Oncol 134(2):325–330

    CAS  Google Scholar 

  • Liu H, Naxerova K, Pinter M, Incio J, Lee H, Shigeta K, Ho WW, Crain JA, Jacobson A, Michelakos T, Dias-Santos D, Zanconato A, Hong TS, Clark JW, Murphy JE, Ryan DP, Deshpande V, Lillemoe KD, Fernandez-del Castillo C, Downes M, Evans RM, Michaelson J, Ferrone CR, Boucher Y, Jain RK(2017) Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin Cancer Res 23(19):5959–5969

    Google Scholar 

  • Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, Ancukiewicz M, Boucher Y, Jain RK, Xu L (2012) TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci U S A:201117610

    Google Scholar 

  • Liu Y, Zhang P, Li F, Jin X, Li J, Chen W, Li Q (2018) Metal-based nanoenhancers for future radiotherapy: radiosensitizing and synergistic effects on tumor cells. Theranostics 8(7):1824

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maenhout SK, Thielemans K, Aerts JL (2014) Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells. Onco Targets Ther 3(10):e956579

    Google Scholar 

  • Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro SP, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T (2018) TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554(7693):544–548

    Google Scholar 

  • Martin JD, Cabral H, Stylianopoulos T, Jain RK (2020) Improving cancer immunotherapy using nanomedicine: progress, opportunities and challenges. Nat Rev Clin Oncol 17:251–266

    Google Scholar 

  • Martin JD, Panagi M, Wang C, Khan TT, Martin MR, Voutouri C, Toh K, Papageorgis P, Mpekris F, Polydorou C, Ishii G, Takahashi S, Gotohda N, Suzuki T, Wilhelm ME, Melo VA, Quader S, Norimatsu J, Lanning RM, Kojima M, Stuber MD, Stylianopoulos T, Kataoka K, Cabral H (2019a) Dexamethasone increases Cisplatin-loaded Nanocarrier delivery and efficacy in metastatic breast cancer by normalizing the tumor microenvironment. ACS Nano 13(6):6396–6408

    CAS  PubMed  Google Scholar 

  • Martin JD, Seano G, Jain RK (2019b) Normalizing function of tumor vessels: Progress, opportunities and challenges. Annu Rev Physiol 81:505–534

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK (2016) Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity. Cold Spring Harb Perspect Med 6(12):a027094

    PubMed  PubMed Central  Google Scholar 

  • Mason K, Hunter N, Terry N, Patel N, Harada S, Jibu T, Seong J, Milas L (1997) Enhanced radioresponse of paclitaxel-sensitive and-resistant tumours in vivo. Eur J Cancer 33(8):1299–1308

    PubMed  Google Scholar 

  • Matsumura Y, Maeda H (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 46(12 Part 1):6387–6392

    CAS  PubMed  Google Scholar 

  • Mazzone M, Bergers G (2019) Regulation of blood and lymphatic vessels by immune cells in tumors and metastasis. Annu Rev Physiol 81:535–560

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragones J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136(5):839–851. https://doi.org/10.1016/j.cell.2009.01.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meijer TW, Kaanders JH, Span PN, Bussink J (2012) Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. AACR

    Google Scholar 

  • Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 2(9):992–997

    CAS  PubMed  Google Scholar 

  • Mi P, Kokuryo D, Cabral H, Wu H, Terada Y, Saga T, Aoki I, Nishiyama N, Kataoka K (2016) A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat Nanotechnol 11(8):724–730

    CAS  PubMed  Google Scholar 

  • Milas L (2009) Principles of combining radiation therapy and chemotherapy, chap 4. In: Radiation oncolgy: rationale, technique, results, pp 102–117. https://www.amazon.com/Radiation-Oncology-Rationale-Technique-Results/dp/0323049710

  • Milas L, Hunter N, Mason KA, Milross C, Peters LJ (1995) Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse. Acta Oncol 34(3):409–412

    CAS  PubMed  Google Scholar 

  • Miller MA, Chandra R, Cuccarese MF, Pfirschke C, Engblom C, Stapleton S, Adhikary U, Kohler RH, Mohan JF, Pittet MJ (2017) Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci Transl Med 9(392):eaal0225

    PubMed  PubMed Central  Google Scholar 

  • Min Y, Roche KC, Tian S, Eblan MJ, McKinnon KP, Caster JM, Chai S, Herring LE, Zhang L, Zhang T (2017) Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat Nanotechnol 12(9):877–882

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160(3):985–1000

    PubMed  PubMed Central  Google Scholar 

  • Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M (2019) Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1103–1115

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mpekris F, Baish JW, Stylianopoulos T, Jain RK (2017) Role of vascular normalization in benefit from metronomic chemotherapy. Proc Natl Acad Sci U S A 114(8):1994–1999

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mpekris F, Voutouri C, Baish JW, Duda DG, Munn LL, Stylianopoulos T, Jain RK (2020) Combining microenvironment normalization strategies to improve cancer immunotherapy. Proc Natl Acad Sci U S A 117:3728–3737

    Google Scholar 

  • Müller P, Rothschild SI, Arnold W, Hirschmann P, Horvath L, Bubendorf L, Savic S, Zippelius A (2016) Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells. Cancer Immunol Immunother 65(1):1–11

    PubMed  Google Scholar 

  • Munn LL, Jain RK (2019) Vascular regulation of anti-tumor immunity. Science 365(6453):544–555

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murphy JE, Wo JY-L, Ryan DP, Clark JW, Jiang W, Yeap BY, Drapek LC, Ly L, Baglini CV, Blaszkowsky L, Ferrone C, Parikh AR, Weekes C, Nipp RD, Kwak EL, Allen JN, Corcoran RB, Ting DT, Faris JE, Zhu AX, Goyal L, Berger DL, Qadan M, Lillemoe KD, Talele N, Jain RK, Delaney TF, Duda DG, Boucher Y, Fernandez-del Castillo C, Hong TS (2019) A phase II study of neoadjuvant FOLFIRINOX in combination with losartan followed by chemoradiotherapy in locally advanced pancreatic cancer: R0 resection rate and clinical outcomes. JAMA Oncol 5(7):1020–1027

    PubMed  PubMed Central  Google Scholar 

  • Netti PA, Berk DA, Swartz MA, Grodzinsky AJ, Jain RK (2000) Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res 60(9):2497–2503

    CAS  PubMed  Google Scholar 

  • Netti PA, Hamberg LM, Babich JW, Kierstead D, Graham W, Hunter GJ, Wolf GL, Fischman A, Boucher Y, Jain RK (1999) Enhancement of fluid filtration across tumor vessels: implication for delivery of macromolecules. Proc Natl Acad Sci U S A 96(6):3137–3142

    CAS  PubMed  PubMed Central  Google Scholar 

  • Netti PA, Roberge S, Boucher Y, Baxter LT, Jain RK (1996) Effect of transvascular fluid exchange on pressure-flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity. Microvasc Res 52(1):27–46. https://doi.org/10.1006/mvre.1996.0041

    Article  CAS  PubMed  Google Scholar 

  • Nishimura Y (2004) Rationale for chemoradiotherapy. Int J Clin Oncol 9(6):414–420

    PubMed  Google Scholar 

  • Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S (2014) PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211(5):781–790

    CAS  PubMed  PubMed Central  Google Scholar 

  • Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B, Chouaib S (2015) Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am J Phys Cell Phys 309(9):C569–C579

    Google Scholar 

  • Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 214(3):579–596

    PubMed  PubMed Central  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D (2009) Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461

    CAS  PubMed  PubMed Central  Google Scholar 

  • Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Pathology: cancer cells compress intratumour vessels. Nature 427(6976):695. https://doi.org/10.1038/427695a

    Article  CAS  PubMed  Google Scholar 

  • Palazon A, Tyrakis PA, Macias D, Veliça P, Rundqvist H, Fitzpatrick S, Vojnovic N, Phan AT, Loman N, Hedenfalk I (2017) An HIF-1α/VEGF-A Axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32(5):669–683. e665

    CAS  PubMed  PubMed Central  Google Scholar 

  • Panagi M, Voutouri C, Mpekris F, Papageorgis P, Martin MR, Martin JD, Polydorou C, Louca M, Kataoka K, Cabral H, Stylianopoulos T (2020) TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity. Theranostics 10:1910–1922

    Google Scholar 

  • Papageorgis P, Polydorou C, Mpekris F, Voutouri C, Agathokleous E, Kapnissi-Christodoulou CP, Stylianopoulos T (2017) Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo-and nanotherapeutics in a size-independent manner. Sci Rep:7, 46140

    Google Scholar 

  • Patan S, Munn LL, Jain RK (1996) Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis. Microvasc Res 51(2):260–272. https://doi.org/10.1006/mvre.1996.0025

    Article  CAS  PubMed  Google Scholar 

  • Patan S, Munn LL, Tanda S, Roberge S, Jain RK, Jones RC (2001a) Vascular morphogenesis and remodeling in a model of tissue repair: blood vessel formation and growth in the ovarian pedicle after ovariectomy. Circ Res 89(8):723–731

    CAS  PubMed  Google Scholar 

  • Patan S, Tanda S, Roberge S, Jones RC, Jain RK, Munn LL (2001b) Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation. Circ Res 89(8):732–739

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peng J, Xiao Y, Li W, Yang Q, Tan L, Jia Y, Qu Y, Qian Z (2018) Photosensitizer micelles together with IDO inhibitor enhance cancer photothermal therapy and immunotherapy. Advanced Science 5(5):1700891

    PubMed  PubMed Central  Google Scholar 

  • Philip B, Ito K, Moreno-Sanchez R, Ralph SJ (2013) HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis 34(8):1699–1707. https://doi.org/10.1093/carcin/bgt209

    Article  CAS  PubMed  Google Scholar 

  • Pinter M, Jain RK (2017) Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci Transl Med 9(410):eaan5616

    PubMed  PubMed Central  Google Scholar 

  • Pitroda SP, Chmura SJ, Weichselbaum RR (2019) Integration of radiotherapy and immunotherapy for treatment of oligometastases. Lancet Oncol 20(8):e434–e442

    CAS  PubMed  Google Scholar 

  • Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378(2):158–168

    CAS  PubMed  Google Scholar 

  • Quintela-Fandino M, Lluch A, Manso LM, Calvo I, Cortes J, García-Saenz JA, Gil JM, Martinez-Jañez N, González-Martín A, Adrover E (2016) 18F-fluoromisonidazole PET and activity of neoadjuvant nintedanib in early HER2-negative breast cancer: a window-of-opportunity randomized trial.. American Association for Cancer Research:clincanres. 0738.2016

    Google Scholar 

  • Rafii S, Lyden D, Benezra R, Hattori K, Heissig B (2002) Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer 2(11):826–835

    CAS  PubMed  Google Scholar 

  • Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW, Nia HT, Edrich CM, Jung K, Daubriac J, Chen I, Heishi T, Martin JD, Huang Y, Maimon N, Reissfelder C, Weitz J, Boucher Y, Clark JW, Grodzinsky AJ, Duda DG, Jain RK, Fukumura D (2016) Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci Transl Med 8(360):360ra135–360ra135

    Google Scholar 

  • Ramanathan RK, Korn R, Raghunand N, Sachdev JC, Newbold RG, Jameson G, Fetterly GJ, Prey J, Klinz SG, Kim J (2017) Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: a pilot study. Clin Cancer Res 23(14):3638–3648

    CAS  PubMed  Google Scholar 

  • Regan DP, Coy JW, Chahal KK, Chow L, Kurihara JN, Guth AM, Kufareva I, Dow SW (2019) The angiotensin receptor blocker losartan suppresses growth of pulmonary metastases via AT1R-independent inhibition of CCR2 Signaling and monocyte recruitment. J Immunol 202(10):3087–3102

    CAS  PubMed  Google Scholar 

  • Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468(7325):824–828. https://doi.org/10.1038/nature09557

    Article  CAS  PubMed  Google Scholar 

  • Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B (2019) Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1116–1127

    CAS  PubMed  Google Scholar 

  • Rockwell S, Dobrucki IT, Kim EY, Marrison ST, Vu VT (2009) Hypoxia and radiation therapy: past history, ongoing research, and future promise. Curr Mol Med 9(4):442–458

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodríguez-Ruiz ME, Vanpouille-Box C, Melero I, Formenti SC, Demaria S (2018) Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol 39(8):644–655

    PubMed  PubMed Central  Google Scholar 

  • Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19(1):31–44

    CAS  PubMed  Google Scholar 

  • Rytelewski M, Haryutyunan K, Nwajei F, Shanmugasundaram M, Wspanialy P, Zal MA, Chen C-H, El Khatib M, Plunkett S, Vinogradov SA (2019) Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors. J Immunother Cancer 7(1):78

    PubMed  PubMed Central  Google Scholar 

  • Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon DT, Greten FR, Hingorani SR, Hunter T, Hynes RO, Jain RK, Janowitz T, Jorgensen C, Kimmelman AC, Kolonin M, Maki RG, Powers S, Pure E, Ramirez D, Scherz-Shouval R, Sherman MH, Stewart S, Tlsty TD, Tuveson DA, Watt FM, Weaver VM, Weeraratna A, Werb Z (2020) A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 20:174–186

    Google Scholar 

  • Sajithlal GB, McGuire TF, Lu J, Beer-Stolz D, Prochownik EV (2010) Endothelial-like cells derived directly from human tumor xenografts. Int J Cancer 127(10):2268–2278. https://doi.org/10.1002/ijc.25251

    Article  CAS  PubMed  Google Scholar 

  • Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean M-C, Validire P, Trautmann A, Mami-Chouaib F, Donnadieu E (2012) Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 122(3):899

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2(12):758–770

    PubMed  Google Scholar 

  • Schmittnaegel M, Rigamonti N, Kadioglu E, Cassará A, Rmili CW, Kiialainen A, Kienast Y, Mueller H-J, Ooi C-H, Laoui D (2017) Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med 9(385):eaak9670

    PubMed  Google Scholar 

  • Seano G, Jain RK (2020) Vessel co-option in glioblastoma: emerging insights and opportunities. Angiogenesis 23:9–16

    Google Scholar 

  • Semenza GL (2016) Dynamic regulation of stem cell specification and maintenance by hypoxia-inducible factors. Mol Asp Med 47-48:15–23. https://doi.org/10.1016/j.mam.2015.09.004

    Article  CAS  Google Scholar 

  • Sevick EM, Jain RK (1989a) Geometric resistance to blood flow in solid tumors perfused ex vivo: effects of tumor size and perfusion pressure. Cancer Res 49(13):3506–3512

    CAS  PubMed  Google Scholar 

  • Sevick EM, Jain RK (1989b) Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity. Cancer Res 49(13):3513–3519

    CAS  PubMed  Google Scholar 

  • Shamay Y, Elkabets M, Li H, Shah J, Brook S, Wang F, Adler K, Baut E, Scaltriti M, Jena PV (2016) P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci Transl Med 8(345):345ra387-345ra387

    Google Scholar 

  • Sharabi AB, Lim M, DeWeese TL, Drake CG (2015) Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16(13):e498–e509

    PubMed  Google Scholar 

  • Sheridan C (2019) Pancreatic cancer provides testbed for first mechanotherapeutics. Nat Biotechnol 37(8):829

    CAS  PubMed  Google Scholar 

  • Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, Connor F, Van Dyke T, Kozlov S, Martin P, Tseng TW, Dawson DW, Donahue TR, Masamune A, Shimosegawa T, Apte MV, Wilson JS, Ng B, Lau SL, Gunton JE, Wahl GM, Hunter T, Drebin JA, O'Dwyer PJ, Liddle C, Tuveson DA, Downes M, Evans RM (2014) Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159(1):80–93. https://doi.org/10.1016/j.cell.2014.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shigeta K, Datta M, Hato T, Kitahara S, Chen IX, Matsui A, Kikuchi H, Mamessier E, Aoki S, Ramjiawan RR, Ochiai H, Bardeesy N, Huang P, Cobbold M, Zhu AX, Jain RK, Duda DG (2019) Dual Programmed Death Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma. Hepatology 71:1247–1261

    Google Scholar 

  • Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70(15):6171–6180

    CAS  PubMed  PubMed Central  Google Scholar 

  • Siemens DR, Hu N, Sheikhi AK, Chung E, Frederiksen LJ, Pross H, Graham CH (2008) Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res 68(12):4746–4753

    CAS  PubMed  Google Scholar 

  • Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288–2301

    CAS  PubMed  Google Scholar 

  • Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H, Pastorino S, Yang M, Hoffman RM, Kesari S, Verma IM (2011) Feature article: transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci U S A 108(11):4274–4280. https://doi.org/10.1073/pnas.1016030108

    Article  PubMed  PubMed Central  Google Scholar 

  • Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, di Tomaso E, Duda DG, Jain RK (2009) A "vascular normalization index" as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res 69(13):5296–5300. https://doi.org/10.1158/0008-5472.CAN-09-0814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, Wang M, Wen PY, Ivy P, Batchelor TT (2012) Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 72(2):402–407

    CAS  PubMed  Google Scholar 

  • Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, Demeure MJ, Von Hoff D, Hingorani SR, Palculict TB, Izzo J (2013) Hypoxia triggers hedgehog-mediated tumor–stromal interactions in pancreatic cancer. Cancer Res 73(11):3235–3247

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stapleton S, Allen C, Pintilie M, Jaffray DA (2013) Tumor perfusion imaging predicts the intra-tumoral accumulation of liposomes. J Control Release 172(1):351–357

    CAS  PubMed  Google Scholar 

  • Stapleton S, Dunne M, Milosevic M, Tran CW, Gold MJ, Vedadi A, McKee T, Ohashi PS, Allen C, Jaffray DA (2018) Radiation and heat improve the delivery and efficacy of nanotherapeutics by modulating intra-tumoral fluid dynamics. ACS Nano 12(8):7583–7600

    CAS  PubMed  Google Scholar 

  • Stone HB, Bernhard EJ, Coleman CN, Deye J, Capala J, Mitchell JB, Brown JM (2016) Preclinical data on efficacy of 10 drug-radiation combinations: evaluations, concerns, and recommendations. Transl Oncol 9(1):46–56

    PubMed  PubMed Central  Google Scholar 

  • Stylianopoulos T, Jain RK (2013) Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci U S A 110(46):18632–18637. https://doi.org/10.1073/pnas.1318415110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stylianopoulos T, Martin JD, Chauhan VP, Jain SR, Diop-Frimpong B, Bardeesy N, Smith BL, Ferrone CR, Hornicek FJ, Boucher Y, Munn LL, Jain RK (2012) Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc Natl Acad Sci U S A 109(38):15101–15108. https://doi.org/10.1073/pnas.1213353109

    Article  PubMed  PubMed Central  Google Scholar 

  • Stylianopoulos T, Martin JD, Snuderl M, Mpekris F, Jain SR, Jain RK (2013) Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res 73(13):3833–3841. https://doi.org/10.1158/0008-5472.CAN-12-4521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stylianopoulos T, Munn LL, Jain RK (2018) Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer 4(4):292–319

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun C, Jain RK, Munn LL (2007) Non-uniform plasma leakage affects local hematocrit and blood flow: implications for inflammation and tumor perfusion. Ann Biomed Eng 35(12):2121–2129

    PubMed  PubMed Central  Google Scholar 

  • Suzuki M, Nakamatsu K, Kanamori S, Masunaga S-I, Nishimura Y (2003) Additive effects of radiation and docetaxel on murine SCCVII tumors in vivo: special reference to changes in the cell cycle. Radiat Res 159(6):799–804

    CAS  PubMed  Google Scholar 

  • Taggart D, Andreou T, Scott KJ, Williams J, Rippaus N, Brownlie RJ, Ilett EJ, Salmond RJ, Melcher A, Lorger M (2018) Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Proc Natl Acad Sci U S A 115(7):E1540–E1549

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tauriello DV, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Cañellas A, Hernando-Momblona X (2018) TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554(7693):538–543

    CAS  PubMed  Google Scholar 

  • Thariat J, Laé M, Carrère S, Papai Z, Ducassou A, Rochaix P, Sapi Z, Birtwisle-Peyrottes I, Shen CJ, Fernando NH (2019) Antitumor immune response induced by NBTXR3 activated by radiotherapy. ASCO Annual Meeting 2019

    Google Scholar 

  • Thienpont B, Steinbacher J, Zhao H, D’Anna F, Kuchnio A, Ploumakis A, Ghesquière B, Van Dyck L, Boeckx B, Schoonjans L (2016) Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537:63

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tian L, Goldstein A, Wang H, Lo HC, Kim IS, Welte T, Sheng K, Dobrolecki LE, Zhang X, Putluri N (2017) Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544(7649):250–254

    CAS  PubMed  PubMed Central  Google Scholar 

  • Togashi Y, Shitara K, Nishikawa H (2019) Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol 16:356–371

    CAS  PubMed  Google Scholar 

  • Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G, Ancukiewicz M, Barry WT, Goel S, 1430 Lahdenrata J, Isakoff SJ, Yeh ED, Jain SR, Golshan M, Brock J, Snuderl M, Winer EP, Krop IE, Jain RK (2015) Role of vascular density and normalization in response to 1431 neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc Natl Acad Sci U S 1432 A 112(46):14325–14330

    Google Scholar 

  • Tse JM, Cheng G, Tyrrell JA, Wilcox-Adelman SA, Boucher Y, Jain RK, Munn LL (2012) Mechanical compression drives cancer cells toward invasive phenotype. Proc Natl Acad Sci U S A 109(3):911–916. https://doi.org/10.1073/pnas.1118910109

    Article  PubMed  Google Scholar 

  • Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528):568–571

    CAS  PubMed  PubMed Central  Google Scholar 

  • Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520(7547):373–377

    CAS  PubMed  Google Scholar 

  • Ueda S, Kuji I, Shigekawa T, Takeuchi H, Sano H, Hirokawa E, Shimada H, Suzuki H, Oda M, Osaki A (2014) Optical imaging for monitoring tumor oxygenation response after initiation of single-agent bevacizumab followed by cytotoxic chemotherapy in breast cancer patients. PLoS One 9(6):e98715

    PubMed  PubMed Central  Google Scholar 

  • Ueda S, Saeki T, Osaki A, Yamane T, Kuji I (2017) Bevacizumab induces acute hypoxia and cancer progression in patients with refractory breast cancer: multimodal functional imaging and multiplex cytokine analysis. Clin Cancer Res 23(19):5769–5778

    CAS  PubMed  Google Scholar 

  • Ueda S, Saeki T, Takeuchi H, Shigekawa T, Yamane T, Kuji I, Osaki A (2016) In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer 114:1212

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, Inghirami G, Coleman CN, Formenti SC, Demaria S (2017) DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8:15618

    PubMed  PubMed Central  Google Scholar 

  • Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, Babb JS, Formenti SC, Barcellos-Hoff MH, Demaria S (2015) TGFβ is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res 75(11):2232–2242

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vasudev NS, Reynolds AR (2014) Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17(3):471–494. https://doi.org/10.1007/s10456-014-9420-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veglia F, Gabrilovich DI (2017) Dendritic cells in cancer: the role revisited. Curr Opin Immunol 45:43–51

    CAS  PubMed  PubMed Central  Google Scholar 

  • Viallard C, Larrivée B (2017) Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 20(4):409–426

    CAS  PubMed  Google Scholar 

  • Vokes EE, Weichselbaum RR (1990) Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 8(5):911–934

    CAS  PubMed  Google Scholar 

  • Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet A-L, Latreche S, Bergaya S, Benhamouda N, Tanchot C (2015) VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 212(2):139–148

    CAS  PubMed  PubMed Central  Google Scholar 

  • Voutouri C, Kirkpatrick ND, Chung E, Mpekris F, Baish JW, Munn LL, Fukumura D, Stylianopoulos T, Jain RK (2019) Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies. Proc Natl Acad Sci U S A:201818322

    Google Scholar 

  • Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS (2016) Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 7:12624

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468(7325):829–833. https://doi.org/10.1038/nature09624

    Article  CAS  PubMed  Google Scholar 

  • Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini G (1992) Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst 84(24):1875–1887. https://doi.org/10.1093/jnci/84.24.1875

    Article  CAS  PubMed  Google Scholar 

  • Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410. https://doi.org/10.1038/nrc3064

    Article  CAS  PubMed  Google Scholar 

  • Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6(6):553–563. https://doi.org/10.1016/j.ccr.2004.10.011

    Article  CAS  PubMed  Google Scholar 

  • Yuan F, Salehi HA, Boucher Y, Vasthare US, Tuma RF, Jain RK (1994) Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res 54(17):4564–4568

    CAS  PubMed  Google Scholar 

  • Zheng X, Fang Z, Liu X, Deng S, Zhou P, Wang X, Zhang C, Yin R, Hu H, Chen X (2018) Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. J Clin Invest 128(5):2104–2115

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This book chapter is based on our recent review articles (Martin et al. 2020, Martin et al. 2019b). The research leading to these results has received funding from the National Foundation for Cancer Research; the Ludwig Center at Harvard; the Jane’s Trust Foundation; the Advanced Medical Research Foundation, the U.S. National Cancer Institute grants R35-CA197743, R01-CA208205, and U01-CA224348 and the U.S. Department of Defense Breast Cancer Research Program Innovator Award W81XWH-10-1-0016 (to R.K.J.).

Competing Interests

R.K.J. has received honoraria from Amgen, has acted as a consultant of Chugai, Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit, owns equity in Enlight, Ophthotech, and SynDevRx, and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. J.D.M is an employee of NanoCarrier Co.

Author information

Authors and Affiliations

  1. NanoCarrier Co. Ltd., Kashiwa, Chiba, Japan

    John D. Martin

  2. Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Rakesh K. Jain

Authors
  1. John D. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakesh K. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rakesh K. Jain .

Editor information

Editors and Affiliations

  1. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Henning Willers

  2. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA

    Iris Eke

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Martin, J.D., Jain, R.K. (2020). Normalizing the Tumor Microenvironment for Radiosensitization. In: Willers, H., Eke, I. (eds) Molecular Targeted Radiosensitizers. Cancer Drug Discovery and Development. Humana, Cham. https://doi.org/10.1007/978-3-030-49701-9_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-49701-9_12

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-49700-2

  • Online ISBN: 978-3-030-49701-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation