Abstract
Background: The ongoing acquisition of genetic alterations in individual cancer cells leads to the emergence of genetically distinct tumor subclones. In concert with selective forces imposed on cancer cells by environmental factors, this drives tumor evolution. The stochastic nature of genetic events and the cellular adaption in response to external signals induces the formation of biologicallyheterogeneous tumor subclones. This intra-tumor cell heterogeneity (ITH) underlies the intrinsic (primary) and acquired (secondary) resistance to therapy that is commonly observed in patients with cancer and represents a major challenge for cancer (immuno-) therapy. Here we review the multiple dimensions of ITH, its impact on therapy resistance and existing approaches to overcome this still underappreciated therapeutic challenge.
Methods: A selective literature review was performed using PubMed (keywords: “intratumor heterogeneity”; “tumor heterogeneity”).
Results: ITH is a multilevel phenomenon that far exceeds genetic variation between tumor subclones alone. The tumor cells’ macro- and microenvironment contribute to epigenetic and metabolic alterations and induce phenotypic diversity between cancer cells of single lesions and of different tissue sites. Importantly, ITH and anti-tumor immune responses mutually influence each other. The immune system reduces ITH by eliminating immunogenic tumor subclones, while ITH, on the other hand, blunts spontaneous anti-tumor immune responses. ITH is associated with poorer responses to immunotherapy and poorer overall survival, highlighting the need for new therapeutic approaches to improve patient outcomes. While there are promising strategies aimed at reducing ITH, these have yet to prove their usefulness for the treatment of tumors with pronounced ITH.
Conclusions: ITH is increasingly recognized as a major therapeutic challenge in patients with cancer. A better understanding and improved assessment of ITH will enable the prediction of therapy resistance and guide the development of new, more effective treatments.
References
Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R et al (2017) Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545(7655):446–451
Affo S, Nair A, Brundu F, Ravichandra A, Bhattacharjee S, Matsuda M et al (2021) Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39(6):866–882
Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846
Akhmetzyanova I, Aaron T, Galbo P, Tikhonova A, Dolgalev I, Tanaka M et al (2021) Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα. Blood Adv 5(18):3592–3608
Alfaro JA, Sinha A, Kislinger T, Boutros PC (2014) Onco-proteogenomics: cancer proteomics joins forces with genomics. Nat Methods 11(11):1107–1113
Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J et al (2017) Evolution of neoantigen landscape during immune checkpoint blockade in non–small cell lung cancer. Cancer Discovery. 7(3):264–276
Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C, Li X et al (2009) Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res 69(1):369–378
Andor N, Graham TA, Jansen M, Xia LC, Aktipis CA, Petritsch C et al (2016) Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat Med 22(1):105–113
Arnone M, Konantz M, Hanns P, Paczulla Stanger AM, Bertels S, Godavarthy PS et al (2020) Acute myeloid leukemia stem cells: the challenges of phenotypic heterogeneity. Cancers (Basel) 12(12):3742. https://doi.org/10.3390/cancers12123742. PMID 33322769. https://pubmed.ncbi.nlm.nih.gov/33322769/
Bakker ER, Hoekstra E, Franken PF, Helvensteijn W, van Deurzen CH, van Veelen W et al (2013) β-Catenin signaling dosage dictates tissue-specific tumor predisposition in Apc-driven cancer. Oncogene 32(38):4579–4585
Bareiss PM, Paczulla A, Wang H, Schairer R, Wiehr S, Kohlhofer U et al (2013) SOX2 expression associates with stem cell state in human ovarian carcinoma. Cancer Res 73(17):5544–5555
Bayik D, Lathia JD (2021) Cancer stem cell–immune cell crosstalk in tumour progression. Nat Rev Cancer 21(8):526–536
Bennett RL, Bele A, Small EC, Will CM, Nabet B, Oyer JA et al (2019) A mutation in histone H2B represents a new class of oncogenic driver. Cancer Discovery 9(10):1438–1451
Bilich T, Nelde A, Bichmann L, Roerden M, Salih HR, Kowalewski DJ et al (2019) The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy. Blood 133(6):550–565
Bilich T, Nelde A, Bauer J, Walz S, Roerden M, Salih HR et al (2020) Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma. Blood Cancer J 10(2):1–10
Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541–550
Black JR, McGranahan N (2021) Genetic and non-genetic clonal diversity in cancer evolution. Nat Rev Cancer 21(6):379–392
Bochner BR (2003) New technologies to assess genotype–phenotype relationships. Nat Rev Genet 4(4):309–314
Boesch M, Sopper S, Zeimet AG, Reimer D, Gastl G, Ludewig B et al (2016) Heterogeneity of cancer stem cells: rationale for targeting the stem cell niche. Biochimica et Biophysica Acta (BBA)-Rev Cancer 1866(2):276–289
Bozkus CC, Roudko V, Finnigan JP, Mascarenhas J, Hoffman R, Iancu-Rubin C et al (2019) Immune checkpoint blockade enhances shared neoantigen-induced T-cell immunity directed against mutated calreticulin in myeloproliferative neoplasms. Cancer Discovery 9(9):1192–1207
Brocks D, Assenov Y, Minner S, Bogatyrova O, Simon R, Koop C et al (2014) Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep 8(3):798–806
Burger ML, Cruz AM, Crossland GE, Gaglia G, Ritch CC, Blatt SE, et al. Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Cell 2021;184(19):4996-5014. e26.
Carter B, Zhao K (2021) The epigenetic basis of cellular heterogeneity. Nat Rev Genet 22(4):235–250
Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38(9):1043–1048
Casanova-Acebes M, Dalla E, Leader AM, LeBerichel J, Nikolic J, Morales BM et al (2021) Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature. (595.7868 (2021): 578-584.)
Caswell DR, Swanton C (2017) The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome. BMC Med 15(1):1–9
Chao M, Seita J, Weissman I, editors. Establishment of a normal hematopoietic and leukemia stem cell hierarchy. Cold Spring Harbor symposia on quantitative biology; 2008: Cold Spring Harbor Laboratory Press.
Chatterjee A, Rodger EJ, Eccles MR (2018) Epigenetic drivers of tumourigenesis and cancer metastasis. Semin Cancer Biol 51:149–159. https://doi.org/10.1016/j.semcancer.2017.08.004. Epub 2017 Aug 12. PMID: 28807546
Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1):1–10
Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z et al (2009) PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15(1):21–34
Darvin P, Toor SM, Nair VS, Elkord E (2018) Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 50(12):1–11
Darwin C (1876) The origin of species by means of natural selection, or, the preservation of favoured races in the struggle for life. John Murray publishing, London, UK
Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1):12–27
de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L et al (2014) Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346(6206):251–256
Dentro SC, Leshchiner I, Haase K, Tarabichi M, Wintersinger J, Deshwar AG et al (2021) Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184(8):2239–54. e39
Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A (2016) Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer 15(1):69
Dong Z, Cui H, editors (2019) Epigenetic modulation of metabolism in glioblastoma. Seminars in cancer biology. Elsevier. PMID 30205139. https://pubmed.ncbi.nlm.nih.gov/30205139/
Dongre A, Weinberg RA (2019) New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20(2):69–84
Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148
Duong E, Fessenden TB, Lutz E, Dinter T, Yim L, Blatt S, et al (2022) Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity. Immunity. PMID 34800368. https://pubmed.ncbi.nlm.nih.gov/34800368/
DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T (2012) Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482(7385):405–409
Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH et al (2016) Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537(7621):539–543
Engblom C, Pfirschke C, Pittet MJ (2016) The role of myeloid cells in cancer therapies. Nat Rev Cancer 16(7):447–462
Fang D, Gan H, Lee J-H, Han J, Wang Z, Riester SM et al (2016) The histone H3. 3K36M mutation reprograms the epigenome of chondroblastomas. Science 352(6291):1344–1348
Faubert B, Solmonson A, DeBerardinis RJ (2020) Metabolic reprogramming and cancer progression. Science 368(6487):eaaw5473
Feinberg AP, Fallin MD (2015) Epigenetics at the crossroads of genes and the environment. JAMA 314(11):1129–1130
Feinberg AP, Koldobskiy MA, Göndör A (2016) Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet 17(5):284–299
Fu T, Dai L-J, Wu S-Y, Xiao Y, Ma D, Jiang Y-Z et al (2021) Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response. J Hematol Oncol 14(1):1–25
Galbo PM, Zang X, Zheng D (2021) Implication of cancer associated fibroblast subtypes on cancer pathogenesis, prognosis, and immunotherapy resistance. Clin Cancer Res 27(9):2636–2647. https://doi.org/10.1158/1078-0432.CCR-20-4226. Epub 2021 Feb 23. PMID: 33622705. https://pubmed.ncbi.nlm.nih.gov/33622705/
Galon J, Bruni D (2019) Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 18(3):197–218
Gerlinger M, Horswell S, Larkin J, Rowan AJ, Salm MP, Varela I et al (2014) Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat Genet 46(3):225–233
Ghilas S, Mielke LA (2021) Dendritic cells shape TCF1+ CD8+ progenitor T cell heterogeneity. Trends Immunol 42(12):1063–1065. https://doi.org/10.1016/j.it.2021.10.013. Epub 2021 Nov 10. PMID 34774417. https://pubmed.ncbi.nlm.nih.gov/34774417/
Goel A, Mathupala SP, Pedersen PL (2003) Glucose metabolism in cancer: evidence that demethylation events play a role in activating type II hexokinase gene expression. J Biol Chem 278(17):15333–15340
Granot T, Senda T, Carpenter DJ, Matsuoka N, Weiner J, Gordon CL et al (2017) Dendritic cells display subset and tissue-specific maturation dynamics over human life. Immunity 46(3):504–515
Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T et al (2021) Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature:1–6
Gros A, Parkhurst MR, Tran E, Pasetto A, Robbins PF, Ilyas S et al (2016) Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med 22(4):433–438
Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T et al (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515(7528):577–581
Guo M, Peng Y, Gao A, Du C, Herman JG (2019) Epigenetic heterogeneity in cancer. Biomarker Res 7(1):1–19
Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discovery 12(1):31–46
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Hinohara K, Wu H-J, Vigneau S, McDonald TO, Igarashi KJ, Yamamoto KN et al (2018) KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell 34(6):939–53.e9
Horton BL, Fessenden TB, Spranger S (2019) Tissue site and the cancer immunity cycle. Trends Cancer 5(10):593–603
Horton BL, Morgan DM, Momin N, Zagorulya M, Torres-Mejia E, Bhandarkar V et al (2021) Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in non–small cell lung cancer. Science Immunol 6(64):eabi8800
Hu X, Estecio MR, Chen R, Reuben A, Wang L, Fujimoto J et al (2021) Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas. Nat Commun 12(1):1–13
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TB, Veeriah S et al (2017) Tracking the evolution of non–small-cell lung cancer. N Engl J Med 376(22):2109–2121
Junttila MR, De Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501(7467):346–354
Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26(17):2813
Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16(9):582–598
Kim J, DeBerardinis RJ (2019) Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab 30(3):434–446
Kojima M, Harada T, Fukazawa T, Kurihara S, Saeki I, Takahashi S et al (2021) Single-cell DNA and RNA sequencing of circulating tumor cells. Sci Rep 11(1):22864
Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS et al (2016) STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res 76(5):999–1008
Kreso A, O'Brien CA, van Galen P, Gan OI, Notta F, Brown AM et al (2013) Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339(6119):543–548
Lai C, Coltart G, Shapanis A, Healy C, Alabdulkareem A, Selvendran S et al (2021) CD8+ CD103+ tissue-resident memory T cells convey reduced protective immunity in cutaneous squamous cell carcinoma. J Immunother Cancer 9(1):e001807. https://doi.org/10.1136/jitc-2020-001807. PMID 33479027. https://pubmed.ncbi.nlm.nih.gov/33479027/
Lawson DA, Kessenbrock K, Davis RT, Pervolarakis N, Werb Z (2018) Tumour heterogeneity and metastasis at single-cell resolution. Nat Cell Biol 20(12):1349–1360
Leick KM, Pinczewski J, Mauldin IS, Young SJ, Deacon DH, Woods AN et al (2019) Patterns of immune-cell infiltration in murine models of melanoma: roles of antigen and tissue site in creating inflamed tumors. Cancer Immunol Immunother 68(7):1121–1132
Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE et al (2017) Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 20(2):233–46. e7
Lin D-C, Mayakonda A, Dinh HQ, Huang P, Lin L, Liu X et al (2017) Genomic and epigenomic heterogeneity of hepatocellular carcinoma. Cancer Res 77(9):2255–2265
Lodish H, Berk A, Kaiser CA, Kaiser C, Krieger M, Scott MP et al (2008) Molecular cell biology. Macmillan, W. H. Freeman and Company (Macmillan Higher Education), New York City, NY, USA
Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L et al (2016) Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352(6287):844–849
Machida K (2018) Pluripotency transcription factors and metabolic reprogramming of mitochondria in tumor-initiating stem-like cells. Antioxid Redox Signal 28(11):1080–1089
Mao Y, Keller ET, Garfield DH, Shen K, Wang J (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32(1):303–315
Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochimica et Biophysica Acta (BBA)-Rev Cancer 1805(1):105–117
Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12(5):323–334
Marusyk A, Janiszewska M, Polyak K (2020) Intratumor heterogeneity: the rosetta stone of therapy resistance. Cancer Cell 37(4):471–484
Mavragani IV, Nikitaki Z, Souli MP, Aziz A, Nowsheen S, Aziz K et al (2017) Complex DNA damage: a route to radiation-induced genomic instability and carcinogenesis. Cancer 9(7):91
McDonald K-A, Kawaguchi T, Qi Q, Peng X, Asaoka M, Young J et al (2019) Tumor heterogeneity correlates with less immune response and worse survival in breast cancer patients. Ann Surg Oncol 26(7):2191–2199
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351(6280):1463–1469
McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TB, Wilson GA et al (2017) Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171(6):1259–71. e11
Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501(7467):328–337
Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ et al (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359(6377):801–806
Miranda A, Hamilton PT, Zhang AW, Pattnaik S, Becht E, Mezheyeuski A et al (2019) Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc Natl Acad Sci U S A 116(18):9020–9029
Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D et al (2011) Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp Med 208(10):1949–1962
Nobs SP, Kopf M (2021) Tissue-resident macrophages: guardians of organ homeostasis. Trends Immunol 42(6):495–507. https://doi.org/10.1016/j.it.2021.04.007. Epub 2021 May 7. PMID 33972166. https://pubmed.ncbi.nlm.nih.gov/33972166/
Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P et al (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
Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih I-M, Vogelstein B et al (2002) The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci 99(25):16226–16231
Ogawa Y, Masugi Y, Abe T, Yamazaki K, Ueno A, Fujii-Nishimura Y et al (2021) Three distinct stroma types in human pancreatic cancer identified by image analysis of fibroblast subpopulations and collagen. Clin Cancer Res 27(1):107–119
Paczulla AM, Rothfelder K, Raffel S, Konantz M, Steinbacher J, Wang H et al (2019) Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 572(7768):254–259
Paguirigan AL, Smith J, Meshinchi S, Carroll M, Maley C, Radich JP (2015) Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Sci Transl Med 7(281):281re2-re2
Pastore A, Gaiti F, Lu SX, Brand RM, Kulm S, Chaligne R et al (2019) Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL. Nat Commun 10(1):1–11
Pietras K, Östman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316(8):1324–1331
Pietrobon V, Marincola FM (2021) Hypoxia and the phenomenon of immune exclusion. J Transl Med 19(1):9
Plaks V, Kong N, Werb Z (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16(3):225–238
Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423–1437
Queisser A, Hagedorn S, Wang H, Schaefer T, Konantz M, Alavi S et al (2017) Ecotropic viral integration site 1, a novel oncogene in prostate cancer. Oncogene 36(11):1573–1584
Raghavan S, Winter PS, Navia AW, Williams HL, DenAdel A, Lowder KE et al (2021) Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell 184(25):6119–37.e26
Ritchie MD, Holzinger ER, Li R, Pendergrass SA, Kim D (2015) Methods of integrating data to uncover genotype–phenotype interactions. Nat Rev Genet 16(2):85–97
Rodrigues J, Heinrich MA, Teixeira LM, Prakash J (2021) 3D in vitro model (R) evolution: unveiling tumor–stroma interactions. Trends cancer 7(3):249–264
Rosenthal R, Cadieux EL, Salgado R, Al Bakir M, Moore DA, Hiley CT et al (2019) Neoantigen-directed immune escape in lung cancer evolution. Nature 567(7749):479–485
Ross-Innes CS, Becq J, Warren A, Cheetham RK, Northen H, O'Donovan M et al (2015) Whole-genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma. Nat Genet 47(9):1038–1046
Russo M, Crisafulli G, Sogari A, Reilly NM, Arena S, Lamba S et al (2019) Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366(6472):1473–1480
Sahin U, Türeci Ö (2018) Personalized vaccines for cancer immunotherapy. Science 359(6382):1355–1360
Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean M-C, Validire P, Trautmann A et al (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
Scarfò I, Maus MV (2017) Current approaches to increase CAR T cell potency in solid tumors: targeting the tumor microenvironment. J Immunother Cancer 5:28
Scott AC, Dündar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M et al (2019) TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571(7764):270–274
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al (2010) A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141(1):69–80
Shechter R, London A, Schwartz M (2013) Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol 13(3):206–218
Shen J-C, Rideout WM III, Jones PA (1992) High frequency mutagenesis by a DNA methyltransferase. Cell 71(7):1073–1080
Sigalotti L, Fratta E, Coral S, Tanzarella S, Danielli R, Colizzi F et al (2004) Intratumor heterogeneity of cancer/testis antigens expression in human cutaneous melanoma is methylation-regulated and functionally reverted by 5-aza-2′-deoxycytidine. Cancer Res 64(24):9167–9171
Silva JV, Freitas MJ, Fardilha M (2020) Tissue-specific cell signaling. Springer, Springer Nature Switzerland AG 2020. https://link.springer.com/book/10.1007/978-3-030-44436-5#bibliographic-information
Simões RV, Serganova IS, Kruchevsky N, Leftin A, Shestov AA, Thaler HT et al (2015) Metabolic plasticity of metastatic breast cancer cells: adaptation to changes in the microenvironment. Neoplasia 17(8):671–684
Spiegel A, Brooks MW, Houshyar S, Reinhardt F, Ardolino M, Fessler E et al (2016) Neutrophils suppress intraluminal NK cell-mediated tumor cell clearance and enhance extravasation of disseminated carcinoma cells. Cancer Discovery 6(6):630–649
Spranger S (2016) Tumor heterogeneity and tumor immunity: a chicken-and-egg problem. Trends Immunol 37(6):349–351
Spranger S, Bao R, Gajewski TF (2015) Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523(7559):231–235
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J et al (2012) Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487(7408):500–504
Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19(11):1438–1449
Thommen DS, Schumacher TN (2018) T cell dysfunction in cancer. Cancer Cell 33(4):547–562
Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16(5):275–287
Veglia F, Sanseviero E, Gabrilovich DI (2021) Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol 21(8):485–498. https://doi.org/10.1038/s41577-020-00490-y. Epub 2021 Feb 1. PMID 33526920. https://pubmed.ncbi.nlm.nih.gov/33526920/
Vendramin R, Litchfield K, Swanton C (2021) Cancer evolution: Darwin and beyond. EMBO J 40(18):e108389
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013) Cancer genome landscapes. Science 339(6127):1546–1558
Wahl GM, Spike BT (2017) Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity. npj Breast Cancer 3(1):14
Wang H, Schaefer T, Konantz M, Braun M, Varga Z, Paczulla AM et al (2017) Prominent oncogenic roles of EVI1 in breast carcinoma. Cancer Res 77(8):2148–2160
Weinberg RA (2013) The biology of cancer. Garland Science, Taylor & Francis Group, New York City, NY, USA
Weisberg SP, Ural BB, Farber DL (2021) Tissue-specific immunity for a changing world. Cell 184(6):1517–1529
WHO Classification of Tumours (2019) Classification of Tumours Editorial Board, 5th edn. World Health Organization
Wolf Y, Bartok O, Patkar S, Eli GB, Cohen S, Litchfield K et al (2019) UVB-induced tumor heterogeneity diminishes immune response in melanoma. Cell 179(1):219–35. e21
Yan X-J, Xu J, Gu Z-H, Pan C-M, Lu G, Shen Y et al (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43(4):309–315
Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829
Yang W, Lee K-W, Srivastava RM, Kuo F, Krishna C, Chowell D et al (2019) Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat Med 25(5):767–775
Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P et al (2015) Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med 21(7):751–759
Yoo LI, Liu DW, Le Vu S, Bronson RT, Wu H, Yuan J (2006) Pten deficiency activates distinct downstream signaling pathways in a tissue-specific manner. Cancer Res 66(4):1929–1939
Yuan Y (2016) Spatial heterogeneity in the tumor microenvironment. Cold Spring Harbor Perspect Med 6(8):a026583
Zelenay S, van der Veen AG, Böttcher Jan P, Snelgrove Kathryn J, Rogers N, Acton Sophie E et al (2015) Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162(6):1257–1270
Zhao J, Cheng F, Zhao Z (2017) Tissue-specific signaling networks rewired by major somatic mutations in human cancer revealed by proteome-wide discovery. Cancer Res 77(11):2810–2821
Zucman-Rossi J, Jeannot E, Van Nhieu JT, Scoazec JY, Guettier C, Rebouissou S et al (2006) Genotype–phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 43(3):515–524
Acknowledgments
Malte Roerden receives funding from Deutsche Forschungsgemeinschaft (Grant RO 6575/1-1).
Claudia Lengerke receives funding from the European Research Council (ERC CoG Hemstem 866548), The Wilhelm Sander Foundation (2019.042.1), the Deutsche Konsortium für Translationale Krebsforschung (DKTK, RiskY-AML Grant), the Swiss National Science Foundation (179239), and the Deutsche Krebshilfe (Arming NK Cells against AML).
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Roerden, M., Lengerke, C. (2022). Intra-Tumor Cell Heterogeneity: Different Immune Responses for Different Cells. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_40-1
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DOI: https://doi.org/10.1007/978-3-030-80962-1_40-1
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