Skip to main content

Advertisement

SpringerLink
Log in

Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

4-MU:

4-Methylumbelliferone

A2AR:

AMP-elevating A2A adenosine receptors

ATRA:

All-trans retinoic acid

CAFs:

Cancer-associated fibroblasts

CSF-1:

Colony-stimulating factor-1

CTL:

Cytotoxic T lymphocyte

CXCL1:

Chemokine (C-X-C motif) ligand 1

DDR2:

Discoidin domain-containing receptor 2

ECM:

Extracellular matrix

EMT:

Epithelial–mesenchymal transition

FAK:

Focal adhesion kinase

FAP:

Fibroblast activation protein

FSP1:

Fibroblast-specific protein 1

GM-CSF:

Granulocyte-macrophage colony stimulating factor

HA:

Hyaluronic acid

IDO:

Indoleamine 2,3-dioxygenase

LOX:

Lysyl oxidase

MCP1:

Monocyte chemotactic protein-1

MDSCs:

Myeloid derived suppressive cells

MSCs:

Mesenchymal stem cells

PD-L1:

Programmed death-ligand 1

PDAC:

Pancreatic ductal adenocarcinoma

PDGF:

Platelet-derived growth factor

PEGPH20:

PEG-fused hyaluronidase

PGE2:

Prostaglandin E2

PSCs:

Pancreatic stellate cells

ROCK:

Rho-associated protein kinase

SDF-1:

Stromal cell-derived factor 1

SHH:

Sonic hedgehog

SMA:

Smooth muscle actin

STAT3:

Signal transducer and activator of transcription 3

TAMs:

Tumor-associated macrophages

TGF-β:

Transforming growth factor beta

TME:

Tumor microenvironment

Treg :

Regulatory T cells

TSLP:

Thymic stromal lymphopoietin

TuDCs:

Tumor-infiltrating DCs

VDR:

Vitamin D receptor

YAP1:

Yes-associated protein 1

References

  1. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214(2):199–210. doi:10.1002/path.2277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wynn TA, Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18(7):1028–1040. doi:10.1038/nm.2807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16(9):582–598. doi:10.1038/nrc.2016.73

    Article  CAS  PubMed  Google Scholar 

  4. Sugimoto H, Mundel TM, Kieran MW, Kalluri R (2006) Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther 5(12):1640–1646

    Article  CAS  PubMed  Google Scholar 

  5. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401. doi:10.1038/nrc1877

    Article  CAS  PubMed  Google Scholar 

  6. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25(6):719–734. doi:10.1016/j.ccr.2014.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, Westphalen CB, Kitajewski J, Fernandez-Barrena MG, Fernandez-Zapico ME, Iacobuzio-Donahue C, Olive KP, Stanger BZ (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25(6):735–747. doi:10.1016/j.ccr.2014.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Erez N, Truitt M, Olson P, Arron ST, Hanahan D (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17(2):135–147. doi:10.1016/j.ccr.2009.12.041

    Article  CAS  PubMed  Google Scholar 

  9. 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. doi:10.1016/j.cell.2014.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H (2012) The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9(8):454–467. doi:10.1038/nrgastro.2012.115

    Article  CAS  PubMed  Google Scholar 

  11. Davies LC, Heldring N, Kadri N, Le Blanc K (2017) Mesenchymal stromal cell secretion of programmed death-1 ligands regulates T cell mediated immunosuppression. Stem Cells 35(3):766–776. doi:10.1002/stem.2509

    Article  CAS  PubMed  Google Scholar 

  12. de Lourdes Mora-Garcia M, Garcia-Rocha R, Morales-Ramirez O, Montesinos JJ, Weiss-Steider B, Hernandez-Montes J, Avila-Ibarra LR, Don-Lopez CA, Velasco-Velazquez MA, Gutierrez-Serrano V, Monroy-Garcia A (2016) Mesenchymal stromal cells derived from cervical cancer produce high amounts of adenosine to suppress cytotoxic T lymphocyte functions. J Transl Med 14(1):302. doi:10.1186/s12967-016-1057-8

    Article  Google Scholar 

  13. Ino Y, Yamazaki-Itoh R, Oguro S, Shimada K, Kosuge T, Zavada J, Kanai Y, Hiraoka N (2013) Arginase II expressed in cancer-associated fibroblasts indicates tissue hypoxia and predicts poor outcome in patients with pancreatic cancer. PLoS One 8(2):e55146. doi:10.1371/journal.pone.0055146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA, Fearon DT (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110(50):20212–20217. doi:10.1073/pnas.1320318110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330(6005):827–830. doi:10.1126/science.1195300

    Article  CAS  PubMed  Google Scholar 

  16. Lo A, Wang LC, Scholler J, Monslow J, Avery D, Newick K, O’Brien S, Evans RA, Bajor DJ, Clendenin C, Durham AC, Buza EL, Vonderheide RH, June CH, Albelda SM, Pure E (2015) Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res 75(14):2800–2810. doi:10.1158/0008-5472.CAN-14-3041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA (2009) Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4(11):e7965. doi:10.1371/journal.pone.0007965

    Article  PubMed  PubMed Central  Google Scholar 

  18. Simonian PL, Roark CL, Wehrmann F, Lanham AK, Diaz del Valle F, Born WK, O’Brien RL, Fontenot AP (2009) Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol 182(1):657–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Palucka AK, Coussens LM (2016) The basis of oncoimmunology. Cell 164(6):1233–1247. doi:10.1016/j.cell.2016.01.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G (2010) Tumor microenvironments direct the recruitment and expansion of human Th17 cells. J Immunol 184(3):1630–1641. doi:10.4049/jimmunol.0902813

    Article  CAS  PubMed  Google Scholar 

  21. Barnas JL, Simpson-Abelson MR, Brooks SP, Kelleher RJ Jr, Bankert RB (2010) Reciprocal functional modulation of the activation of T lymphocytes and fibroblasts derived from human solid tumors. J Immunol 185(5):2681–2692. doi:10.4049/jimmunol.1000896

    Article  CAS  PubMed  Google Scholar 

  22. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+ CD25- naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886. doi:10.1084/jem.20030152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C, Protti MP (2011) Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med 208(3):469–478. doi:10.1084/jem.20101876

    Article  PubMed  PubMed Central  Google Scholar 

  24. Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41(1):21–35. doi:10.1016/j.immuni.2014.06.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chomarat P, Banchereau J, Davoust J, Palucka AK (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 1(6):510–514. doi:10.1038/82763

    Article  CAS  PubMed  Google Scholar 

  26. Wu MH, Hong HC, Hong TM, Chiang WF, Jin YT, Chen YL (2011) Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin Cancer Res 17(6):1306–1316. doi:10.1158/1078-0432.CCR-10-1824

    Article  CAS  PubMed  Google Scholar 

  27. Torres S, Bartolome RA, Mendes M, Barderas R, Fernandez-Acenero MJ, Pelaez-Garcia A, Pena C, Lopez-Lucendo M, Villar-Vazquez R, de Herreros AG, Bonilla F, Casal JI (2013) Proteome profiling of cancer-associated fibroblasts identifies novel proinflammatory signatures and prognostic markers for colorectal cancer. Clin Cancer Res 19(21):6006–6019. doi:10.1158/1078-0432.CCR-13-1130

    Article  CAS  PubMed  Google Scholar 

  28. Mathew E, Brannon AL, Del Vecchio A, Garcia PE, Penny MK, Kane KT, Vinta A, Buckanovich RJ, di Magliano MP (2016) Mesenchymal stem cells promote pancreatic tumor growth by inducing alternative polarization of macrophages. Neoplasia 18(3):142–151. doi:10.1016/j.neo.2016.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim JH, Oh SH, Kim EJ, Park SJ, Hong SP, Cheon JH, Kim TI, Kim WH (2012) The role of myofibroblasts in upregulation of S100A8 and S100A9 and the differentiation of myeloid cells in the colorectal cancer microenvironment. Biochem Biophys Res Commun 423(1):60–66. doi:10.1016/j.bbrc.2012.05.081

    Article  CAS  PubMed  Google Scholar 

  30. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, Fuchs JR, Eubank TD, Frankel WL, Bekaii-Saab T, Bloomston M, Lesinski GB (2013) Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 73(10):3007–3018. doi:10.1158/0008-5472.CAN-12-4601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Khosravi-Maharlooei M, Pakyari M, Jalili RB, Salimi-Elizei S, Lai JC, Poormasjedi-Meibod M, Kilani RT, Dutz J, Ghahary A (2016) Tolerogenic effect of mouse fibroblasts on dendritic cells. Immunology 148(1):22–33. doi:10.1111/imm.12584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cheng JT, Deng YN, Yi HM, Wang GY, Fu BS, Chen WJ, Liu W, Tai Y, Peng YW, Zhang Q (2016) Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis 5:e198. doi:10.1038/oncsis.2016.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Stromnes IM, Schmitt TM, Hulbert A, Brockenbrough JS, Nguyen HN, Cuevas C, Dotson AM, Tan X, Hotes JL, Greenberg PD, Hingorani SR (2015) T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma. Cancer Cell 28(5):638–652. doi:10.1016/j.ccell.2015.09.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hartmann N, Giese NA, Giese T, Poschke I, Offringa R, Werner J, Ryschich E (2014) Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. Clin Cancer Res 20(13):3422–3433. doi:10.1158/1078-0432.CCR-13-2972

    Article  CAS  PubMed  Google Scholar 

  35. Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, Pachter JA, Wang-Gillam A, DeNardo DG (2016) Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22(8):851–860. doi:10.1038/nm.4123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, 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):899–910. doi:10.1172/JCI45817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wolf K, Te Lindert M, Krause M, Alexander S, Te Riet J, Willis AL, Hoffman RM, Figdor CG, Weiss SJ, Friedl P (2013) Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol 201(7):1069–1084. doi:10.1083/jcb.201210152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. O’Connor RS, Hao X, Shen K, Bashour K, Akimova T, Hancock WW, Kam LC, Milone MC (2012) Substrate rigidity regulates human T cell activation and proliferation. J Immunol 189(3):1330–1339. doi:10.4049/jimmunol.1102757

    Article  PubMed  PubMed Central  Google Scholar 

  39. He J, Baum LG (2004) Presentation of galectin-1 by extracellular matrix triggers T cell death. J Biol Chem 279(6):4705–4712. doi:10.1074/jbc.M311183200

    Article  CAS  PubMed  Google Scholar 

  40. Bollyky PL, Wu RP, Falk BA, Lord JD, Long SA, Preisinger A, Teng B, Holt GE, Standifer NE, Braun KR, Xie CF, Samuels PL, Vernon RB, Gebe JA, Wight TN, Nepom GT (2011) ECM components guide IL-10 producing regulatory T-cell (TR1) induction from effector memory T-cell precursors. Proc Natl Acad Sci USA 108(19):7938–7943. doi:10.1073/pnas.1017360108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McWhorter FY, Davis CT, Liu WF (2015) Physical and mechanical regulation of macrophage phenotype and function. Cell Mol Life Sci 72(7):1303–1316. doi:10.1007/s00018-014-1796-8

    Article  CAS  PubMed  Google Scholar 

  42. Van Goethem E, Poincloux R, Gauffre F, Maridonneau-Parini I, Le Cabec V (2010) Matrix architecture dictates three-dimensional migration modes of human macrophages: differential involvement of proteases and podosome-like structures. J Immunol 184(2):1049–1061. doi:10.4049/jimmunol.0902223

    Article  PubMed  Google Scholar 

  43. Kobayashi N, Miyoshi S, Mikami T, Koyama H, Kitazawa M, Takeoka M, Sano K, Amano J, Isogai Z, Niida S, Oguri K, Okayama M, McDonald JA, Kimata K, Taniguchi S, Itano N (2010) Hyaluronan deficiency in tumor stroma impairs macrophage trafficking and tumor neovascularization. Can Res 70(18):7073–7083. doi:10.1158/0008-5472.CAN-09-4687

    Article  CAS  Google Scholar 

  44. Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, Marconcini LA, Mecham RP, Senior RM, Shapiro SD (2006) Elastin fragments drive disease progression in a murine model of emphysema. J Clin Investig 116(3):753–759. doi:10.1172/JCI25617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, Galin FS, Folkerts G, Nijkamp FP, Blalock JE (2006) A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med 12(3):317–323. doi:10.1038/nm1361

    Article  CAS  PubMed  Google Scholar 

  46. Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C, Chen YY, Liphardt J, Hwang ES, Weaver VM (2015) Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb) 7(10):1120–1134. doi:10.1039/c5ib00040h

    Article  CAS  Google Scholar 

  47. Nielsen SR, Quaranta V, Linford A, Emeagi P, Rainer C, Santos A, Ireland L, Sakai T, Sakai K, Kim YS, Engle D, Campbell F, Palmer D, Ko JH, Tuveson DA, Hirsch E, Mielgo A, Schmid MC (2016) Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat Cell Biol 18(5):549–560. doi:10.1038/ncb3340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF (2013) Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci USA 110(43):17253–17258. doi:10.1073/pnas.1308887110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Springer NL, Fischbach C (2016) Biomaterials approaches to modeling macrophage-extracellular matrix interactions in the tumor microenvironment. Curr Opin Biotechnol 40:16–23. doi:10.1016/j.copbio.2016.02.003

    Article  CAS  PubMed  Google Scholar 

  50. Perri RT, Kay NE, McCarthy J, Vessella RL, Jacob HS, Furcht LT (1982) Fibronectin enhances in vitro monocyte-macrophage-mediated tumoricidal activity. Blood 60(2):430–435

    CAS  PubMed  Google Scholar 

  51. Pickup MW, Mouw JK, Weaver VM (2014) The extracellular matrix modulates the hallmarks of cancer. EMBO Rep 15(12):1243–1253. doi:10.15252/embr.201439246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stahl M, Schupp J, Jager B, Schmid M, Zissel G, Muller-Quernheim J, Prasse A (2013) Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation. PLoS One 8(11):e81382. doi:10.1371/journal.pone.0081382

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wesley RB 2nd, Meng X, Godin D, Galis ZS (1998) Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler Thromb Vasc Biol 18(3):432–440

    Article  CAS  PubMed  Google Scholar 

  54. Meyaard L (2008) The inhibitory collagen receptor LAIR-1 (CD305). J Leukoc Biol 83(4):799–803. doi:10.1189/jlb.0907609

    Article  CAS  PubMed  Google Scholar 

  55. Falanga V, Martin TA, Takagi H, Kirsner RS, Helfman T, Pardes J, Ochoa MS (1993) Low oxygen tension increases mRNA levels of alpha 1 (I) procollagen in human dermal fibroblasts. J Cell Physiol 157(2):408–412. doi:10.1002/jcp.1041570225

    Article  CAS  PubMed  Google Scholar 

  56. Bentovim L, Amarilio R, Zelzer E (2012) HIF1alpha is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development. Development 139(23):4473–4483. doi:10.1242/dev.083881

    Article  CAS  PubMed  Google Scholar 

  57. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24(6):695–709. doi:10.1016/j.ccr.2013.11.007

    Article  CAS  PubMed  Google Scholar 

  59. 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-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211(5):781–790. doi:10.1084/jem.20131916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jiang C, Kim JH, Li F, Qu A, Gavrilova O, Shah YM, Gonzalez FJ (2013) Hypoxia-inducible factor 1alpha regulates a SOCS3-STAT3-adiponectin signal transduction pathway in adipocytes. J Biol Chem 288(6):3844–3857. doi:10.1074/jbc.M112.426338

    Article  CAS  PubMed  Google Scholar 

  61. Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (2008) Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res 14(19):5947–5952. doi:10.1158/1078-0432.CCR-08-0229

    Article  CAS  PubMed  Google Scholar 

  62. Zion O, Genin O, Kawada N, Yoshizato K, Roffe S, Nagler A, Iovanna JL, Halevy O, Pines M (2009) Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas 38(4):427–435. doi:10.1097/MPA.0b013e3181967670

    Article  CAS  PubMed  Google Scholar 

  63. Pines M, Knopov V, Genina O, Lavelin I, Nagler A (1997) Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis. J Hepatol 27(2):391–398

    Article  CAS  PubMed  Google Scholar 

  64. Juarez P, Mohammad KS, Yin JJ, Fournier PG, McKenna RC, Davis HW, Peng XH, Niewolna M, Javelaud D, Chirgwin JM, Mauviel A, Guise TA (2012) Halofuginone inhibits the establishment and progression of melanoma bone metastases. Cancer Res 72(23):6247–6256. doi:10.1158/0008-5472.CAN-12-1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15(1):35–44. doi:10.1016/j.ccr.2008.11.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139(5):891–906. doi:10.1016/j.cell.2009.10.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G, Erler JT (2013) LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res 73(6):1721–1732. doi:10.1158/0008-5472.CAN-12-2233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gilkes DM, Chaturvedi P, Bajpai S, Wong CC, Wei H, Pitcairn S, Hubbi ME, Wirtz D, Semenza GL (2013) Collagen prolyl hydroxylases are essential for breast cancer metastasis. Cancer Res 73(11):3285–3296. doi:10.1158/0008-5472.CAN-12-3963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, McGhee E, Timpson P, Leach J, McGarry L, Shanks E, Bailey P, Chang D, Oien K, Karim S, Au A, Steele C, Carter CR, McKay C, Anderson K, Evans TR, Marais R, Springer C, Biankin A, Erler JT, Sansom OJ (2015) Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med 7(8):1063–1076. doi:10.15252/emmm.201404827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chronopoulos A, Robinson B, Sarper M, Cortes E, Auernheimer V, Lachowski D, Attwood S, Garcia R, Ghassemi S, Fabry B, Del Rio Hernandez A (2016) ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion. Nat Commun 7:12630. doi:10.1038/ncomms12630

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sato N, Cheng XB, Kohi S, Koga A, Hirata K (2016) Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma. Acta Pharm Sin B 6(2):101–105. doi:10.1016/j.apsb.2016.01.002

    Article  PubMed  PubMed Central  Google Scholar 

  72. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429. doi:10.1016/j.ccr.2012.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kultti A, Pasonen-Seppanen S, Jauhiainen M, Rilla KJ, Karna R, Pyoria E, Tammi RH, Tammi MI (2009) 4-Methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp Cell Res 315(11):1914–1923. doi:10.1016/j.yexcr.2009.03.002

    Article  CAS  PubMed  Google Scholar 

  74. Hajime M, Shuichi Y, Makoto N, Masanori Y, Ikuko K, Atsushi K, Mutsuo S, Keiichi T (2007) Inhibitory effect of 4-methylesculetin on hyaluronan synthesis slows the development of human pancreatic cancer in vitro and in nude mice. Int J Cancer 120(12):2704–2709. doi:10.1002/ijc.22349

    Article  CAS  PubMed  Google Scholar 

  75. Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, Solomides CC, June CH, Pure E, Albelda SM (2014) Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2(2):154–166. doi:10.1158/2326-6066.CIR-13-0027

    Article  CAS  PubMed  Google Scholar 

  76. Chen M, Xiang R, Wen Y, Xu G, Wang C, Luo S, Yin T, Wei X, Shao B, Liu N, Guo F, Li M, Zhang S, Li M, Ren K, Wang Y, Wei Y (2015) A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts. Sci Rep 5:14421. doi:10.1038/srep14421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wen Y, Wang CT, Ma TT, Li ZY, Zhou LN, Mu B, Leng F, Shi HS, Li YO, Wei YQ (2010) Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci 101(11):2325–2332. doi:10.1111/j.1349-7006.2010.01695.x

    Article  CAS  PubMed  Google Scholar 

  78. Gottschalk S, Yu F, Ji M, Kakarla S, Song XT (2013) A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLoS One 8(12):e82658. doi:10.1371/journal.pone.0082658

    Article  PubMed  PubMed Central  Google Scholar 

  79. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116(7):1955–1962. doi:10.1172/JCI26532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30(3):245–257. doi:10.1055/s-0030-1255354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Long KB, Gladney WL, Tooker GM, Graham K, Fraietta JA, Beatty GL (2016) IFNgamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma. Cancer Discov 6(4):400–413. doi:10.1158/2159-8290.CD-15-1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zippelius A, Schreiner J, Herzig P, Muller P (2015) Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res 3(3):236–244. doi:10.1158/2326-6066.CIR-14-0226

    Article  CAS  PubMed  Google Scholar 

  83. Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, Clendenin C, Stanger BZ, Furth EE, Wherry EJ, Vonderheide RH (2015) Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol Res 3(4):399–411. doi:10.1158/2326-6066.CIR-14-0215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Ruckert F, Grutzmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461. doi:10.1126/science.1171362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sulzmaier FJ, Jean C, Schlaepfer DD (2014) FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 14(9):598–610. doi:10.1038/nrc3792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rustad KC, Wong VW, Gurtner GC (2013) The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation. Differentiation 86(3):87–91. doi:10.1016/j.diff.2013.02.003

    Article  CAS  PubMed  Google Scholar 

  87. Lagares D, Kapoor M (2013) Targeting focal adhesion kinase in fibrotic diseases. BioDrugs 27(1):15–23. doi:10.1007/s40259-012-0003-4

    Article  CAS  PubMed  Google Scholar 

  88. Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE, Barrett AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, LeBleu VS, Roy N, Novitskiy SV, Johansen JS, Poli V, Kalluri R, Iacobuzio-Donahue CA, Wood LD, Hebrok M, Hansen K, Moses HL, Weaver VM (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22(5):497–505. doi:10.1038/nm.4082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stokes JB, Adair SJ, Slack-Davis JK, Walters DM, Tilghman RW, Hershey ED, Lowrey B, Thomas KS, Bouton AH, Hwang RF, Stelow EB, Parsons JT, Bauer TW (2011) Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther 10(11):2135–2145. doi:10.1158/1535-7163.MCT-11-0261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Serrels A, Lund T, Serrels B, Byron A, McPherson RC, von Kriegsheim A, Gomez-Cuadrado L, Canel M, Muir M, Ring JE, Maniati E, Sims AH, Pachter JA, Brunton VG, Gilbert N, Anderton SM, Nibbs RJ, Frame MC (2015) Nuclear FAK controls chemokine transcription, tregs, and evasion of anti-tumor immunity. Cell 163(1):160–173. doi:10.1016/j.cell.2015.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Box 8069, St. Louis, MO, 63110, USA

    Hong Jiang, Samarth Hegde & David G. DeNardo

  2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    David G. DeNardo

  3. ICCE Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Hong Jiang, Samarth Hegde & David G. DeNardo

  4. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA

    David G. DeNardo

Authors
  1. Hong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samarth Hegde
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David G. DeNardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David G. DeNardo.

Ethics declarations

Funding

The Authors acknowledges support from the Pancreatic Cancer Action Network and the American Association for Cancer Research (AACR/PANCAN Award), the National Cancer Institute (NCI awards R01-CA177670, R01-CA203890, P50-CA196510, P30-CA91842) and the BJCIH/Siteman Cancer Center Cancer Frontier Fund.

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th – 19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, H., Hegde, S. & DeNardo, D.G. Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy. Cancer Immunol Immunother 66, 1037–1048 (2017). https://doi.org/10.1007/s00262-017-2003-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-017-2003-1

Keywords

Search

Navigation