Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response

Abstract

Background: Immune evasion is a fundamental hallmark for cancer. At the early stages of tumor development, immune evasion strategies must be implemented by tumors to prevent attacks from the host immune systems. Blocking tumors’ immune evasion will re-activate the host immune systems to eliminate tumors. Immune-checkpoint therapy (ICT) which applies anti-PD-1/PD-L1 or anti-CTLA4 treatment has been a remarkable success in the past few years. However, ~70% of patients cannot gain any clinical benefits from ICT treatment due to the tumor-immunity system’s complexity. In the past, germline pathogenic variants have been thought to have only minor-heritable contributions to cancer.

Results: Emerging evidence has shown that germline genomes play a dominant-heritable contribution to cancer via encoding the host immune system. The functional components of the immune system are encoded by the host genome, thus the germline genome might have a profound impact on cancer immune evasion and immunotherapy response. Indeed, recent studies showed that germline pathogenic variants can influence immune capacity in cancer patients at a population level by (i) shaping tumor somatic mutations, altering methylation patterns and antigen-presentation capacity or (ii) influencing NK cell’s function to modulate lymphocyte infiltration in the tumor microenvironment. In addition, the HLA (types A, B or C) genotypes also shape the landscape of tumor somatic mutations.

Conclusion: These results highlight the indispensable roles of germline genome in immunity and cancer development and suggest that germline genomics should be integrated into the research field of cancer biology and cancer immunotherapy.

Graphical abstract

Keywords

germline / genomics / cancer / immune evasion / immunotherapy response

References

[1] Hanahan, D. and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646–674

[2] Kriegsman, B. A., Vangala, P., Chen, B. J., Meraner, P., Brass, A. L., Garber, M. and Rock, K. L. (2019) Frequent loss of IRF2 in cancers leads to immune evasion through decreased MHC class I antigen presentation and increased PD-L1 expression. J. Immunol., 203, 1999–2010

[3] Zhang, S., Kohli, K., Black, R. G., Yao, L., Spadinger, S. M., He, Q., Pillarisetty, V. G., Cranmer, L. D., Van Tine, B. A., Yee, C., (2019) Systemic interferon-γ increases MHC class I expression and T-cell infiltration in cold tumors: results of a phase 0 clinical trial. Cancer Immunol. Res., 7, 1237–1243

[4] Lu, Y., Zhang, M., Wang, S., Hong, B., Wang, Z., Li, H., Zheng, Y., Yang, J., Davis, R. E., Qian, J., (2014) p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression. Nat. Commun., 5, 4229

[5] Loi, S., Dushyanthen, S., Beavis, P. A., Salgado, R., Denkert, C., Savas, P., Combs, S., Rimm, D. L., Giltnane, J. M., Estrada, M. V., (2016) RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: Therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin. Cancer Res., 22, 1499–1509

[6] Luke, J. J., Bao, R., Sweis, R. F., Spranger, S. and Gajewski, T. F. (2019) WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin. Cancer Res., 25, 3074–3083

[7] Wang, B., Tian, T., Kalland, K.-H., Ke, X. and Qu, Y. (2018) Targeting Wnt/β-catenin signaling for cancer immunotherapy. Trends Pharmacol. Sci., 39, 648–658

[8] Haslam, A. and 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, e192535

[9] Khair, D. O., Bax, H. J., Mele, S., Crescioli, S., Pellizzari, G., Khiabany, A., Nakamura, M., Harris, R. J., French, E., Hoffmann, R. M., (2019) Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front. Immunol., 10, 453

[10] Chen, D. S. and Mellman, I. (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity, 39, 1–10

[11] Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med., 24, 541–550

[12] Gonzalez, H., Hagerling, C. and Werb, Z. (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev., 32, 1267–1284

[13] Darvin, P., Toor, S. M., Sasidharan Nair, V. and Elkord, E. (2018) Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp. Mol. Med., 50, 1–11

[14] Szabo, C. I. and King, M. C. (1997) Population genetics of BRCA1 and BRCA2. Am. J. Hum. Genet., 60, 1013–1020

[15] Malone, K. E., Daling, J. R., Doody, D. R., Hsu, L., Bernstein, L., Coates, R. J., Marchbanks, P. A., Simon, M. S., McDonald, J. A., Norman, S. A., (2006) Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res., 66, 8297–8308

[16] Bodmer, W. and Tomlinson, I. (2010) Rare genetic variants and the risk of cancer. Curr. Opin. Genet. Dev., 20, 262–267

[17] Knudson, Jr., A. G. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USA, 68, 820–823

[18] Knudson, A. G. (2001) Two genetic hits (more or less) to cancer. Nat. Rev. Cancer, 1, 157–162

[19] Donovan, S. L., Schweers, B., Martins, R., Johnson, D. and Dyer, M. A. (2006) Compensation by tumor suppressor genes during retinal development in mice and humans. BMC Biol., 4, 14

[20] Ajioka, I., Martins, R. A. P., Bayazitov, I. T., Donovan, S., Johnson, D. A., Frase, S., Cicero, S. A., Boyd, K., Zakharenko, S. S. and Dyer, M. A. (2007) Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell, 131, 378–390

[21] Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F. Jr, Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. Z., Tainsky, M. A., (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science, 250, 1233–1238

[22] Kemp, C. J., Wheldon, T. and Balmain, A. (1994) p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat. Genet., 8, 66–69

[23] Lee, J. M., Abrahamson, J. L. A., Kandel, R., Donehower, L. A. and Bernstein, A. (1994) Susceptibility to radiation-carcinogenesis and accumulation of chromosomal breakage in p53 deficient mice. Oncogene, 9, 3731–3736

[24] Levine, A. J., Hu, W. and Feng, Z. (2006) The P53 pathway: what questions remain to be explored? Cell Death Differ., 13, 1027–1036

[25] Maistro, S., Teixeira, N., Encinas, G., Katayama, M. L. H., Niewiadonski, V. D. T., Cabral, L. G., Ribeiro, R. M., Gaburo Junior, N., de Gouvêa, A. C., Carraro, D. M., (2016) Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer, 16, 934

[26] Chan, S. H., Lim, W. K., Ishak, N. D. B., Li, S.-T., Goh, W. L., Tan, G. S., Lim, K. H., Teo, M., Young, C. N. C., Malik, S., (2017) Germline mutations in cancer predisposition genes are frequent in sporadic sarcomas. Sci. Rep., 7, 10660

[27] Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K.-A., Mooij, T. M., Roos-Blom, M.-J., Jervis, S., van Leeuwen, F. E., Milne, R. L., Andrieu, N., (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA, 317, 2402–2416

[28] Liaw, D., Marsh, D. J., Li, J., Dahia, P. L. M., Wang, S. I., Zheng, Z., Bose, S., Call, K. M., Tsou, H. C., Peacoke, M., (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet., 16, 64–67

[29] De Queiroz Rossanese, L. B., De Lima Marson, F. A., Ribeiro, J. D., Coy, C. S. and Bertuzzo, C. S. (2013) APC germline mutations in families with familial adenomatous polyposis. Oncol. Rep., 30, 2081–2088

[30] Washington, K. and Zemper, A. E. D. (2019) Apc-related models of intestinal neoplasia: a brief review for pathologists. Surg. Exp. Pathol., 2, 11

[31] Zeineldin, M. and Neufeld, K. L. (2013) More than two decades of Apc modeling in rodents. Biochim. Biophys. Acta, 1836, 80–89

[32] Moore, L. E., Nickerson, M. L., Brennan, P., Toro, J. R., Jaeger, E., Rinsky, J., Han, S. S., Zaridze, D., Matveev, V., Janout, V., (2011) Von hippel-lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet., 7, e1002312

[33] Gray, P. N., Tsai, P., Chen, D., Wu, S., Hoo, J., Mu, W., Li, B., Vuong, H., Lu, H. M., Batth, N., (2018) TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome. Oncotarget, 9, 20304–20322

[34] Mou, H., Kennedy, Z., Anderson, D. G., Yin, H. and Xue, W. (2015) Precision cancer mouse models through genome editing with CRISPR-Cas9. Genome Med., 7, 53

[35] Guernet, A. and Grumolato, L. (2017) CRISPR/Cas9 editing of the genome for cancer modeling. Methods, 121–122, 130–137

[36] Park, S., Supek, F. and Lehner, B. (2018) Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nat. Commun., 9, 2601

[37] Huang, K. L., Mashl, R. J., Wu, Y., Ritter, D. I., Wang, J., Oh, C., Paczkowska, M., Reynolds, S., Wyczalkowski, M. A., Oak, N., (2018) Pathogenic germline variants in 10,389 adult cancers. Cell, 173, 355–370.e14

[38] Kilpivaara, O. and Aaltonen, L. A. (2013) Diagnostic cancer genome sequencing and the contribution of germline variants. Science, 339, 1559–1562

[39] Wang, E., Zaman, N., Mcgee, S., Milanese, J.-S., Masoudi-Nejad, A. and O’Connor-McCourt, M. (2015) Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data. Semin. Cancer Biol., 30, 4–12

[40] Sever, R. and Brugge, J. S. (2015) Signal transduction in cancer. Cold Spring Harb. Perspect. Med., 5, a006098–a006098

[41] Wellenstein, M. D. and de Visser, K. E. (2018) Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity, 48, 399–416

[42] Nguyen, K. B. and Spranger, S. (2020) Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling. J. Cell Biol., 219, e201908224

[43] Lim, Y. W., Chen-Harris, H., Mayba, O., Lianoglou, S., Wuster, A., Bhangale, T., Khan, Z., Mariathasan, S., Daemen, A., Reeder, J., (2018) Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration. Proc. Natl. Acad. Sci. USA, 115, E11701–E11710

[44] Robinson, J., Halliwell, J. A., Hayhurst, J. D., Flicek, P., Parham, P. and Marsh, S. G. E. (2015) The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res., 43, D423–D431

[45] Marty, R., Kaabinejadian, S., Rossell, D., Slifker, M. J., van de Haar, J., Engin, H. B., de Prisco, N., Ideker, T., Hildebrand, W. H., Font-Burgada, J., (2017) MHC-I genotype restricts the oncogenic mutational landscape. Cell, 171, 1272–1283.e15

[46] Wang, E., Zou, J., Zaman, N., Beitel, L. K., Trifiro, M. and Paliouras, M. (2013) Cancer systems biology in the genome sequencing era: part 2, evolutionary dynamics of tumor clonal networks and drug resistance. Semin. Cancer Biol., 23, 286–292

[47] Wang, E., Zou, J., Zaman, N., Beitel, L. K., Trifiro, M. and Paliouras, M. (2013) Cancer systems biology in the genome sequencing era: part 1, dissecting and modeling of tumor clones and their networks. Semin. Cancer Biol., 23, 279–285

[48] Milanese J.-S., Tibiche C., Zou J., Meng Z., Nantel A., Drouin S., Marcotte R., and Wang E. (2019) Germline variants associated with leukocyte genes predict tumor recurrence in breast cancer patients. NPJ Precis. Oncol., 3, 28

[49] Parsons, B. L. (2008) Many different tumor types have polyclonal tumor origin: evidence and implications. Mutat. Res., 659, 232–247

[50] Parsons, B. L. (2018) Multiclonal tumor origin: evidence and implications. Mutat. Res., 777, 1–18

[51] Knudson, A. G. Jr. (1973) Mutation and human cancer. Adv. Cancer Res., 17, 317–352

[52] Nowell, P. C. (1976) The clonal evolution of tumor cell populations. Science, 194, 23–28

[53] Fearon, E. R., Hamilton, S. R. and Vogelstein, B. (1987) Clonal analysis of human colorectal tumors. Science, 238, 193–197

[54] Vogelstein, B., Fearon, E. R., Hamilton, S. R. and Feinberg, A. P. (1985) Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science, 227, 642–645

[55] Ross, E. M. and Markowetz, F. (2016) OncoNEM: inferring tumor evolution from single-cell sequencing data. Genome Biol., 17, 69

[56] Hou, Y., Song, L., Zhu, P., Zhang, B., Tao, Y., Xu, X., Li, F., Wu, K., Liang, J., Shao, D., (2012) Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm. Cell, 148, 873–885

[57] Xu, X., Hou, Y., Yin, X., Bao, L., Tang, A., Song, L., Li, F., Tsang, S., Wu, K., Wu, H., (2012) Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell, 148, 886–895

[58] Shi, X., Chakraborty, P. and Chaudhuri, A. (2018) Unmasking tumor heterogeneity and clonal evolution by single-cell analysis. J. Cancer Metastasis Treat., 4, 47

[59] Milanese, J., Tibiche, C., Zaman, N., Zou, J., Han, P., Meng, Z., Nantel, A., Droit, A. and Wang, E. (2020) eTumorMetastasis, a network-based algorithm predicts clinical outcomes using whole-exome sequencing data of cancer patients. Genom. Proteom. Bioinfor., (In press)

[60] Li, J., Lenferink, A. E. G., Deng, Y., Collins, C., Cui, Q., Purisima, E. O., O’Connor-McCourt, M. D. and Wang, E. (2010) Identification of high-quality cancer prognostic markers and metastasis network modules. Nat. Commun., 1, 34

[61] Gao, S., Tibiche, C., Zou, J., Zaman, N., Trifiro, M., O’Connor-McCourt, M. and Wang, E. (2016) Identification and construction of combinatory cancer hallmark-based gene signature sets to predict recurrence and chemotherapy benefit in stage II colorectal cancer. JAMA Oncol., 2, 37–45

[62] Toi, M., Iwata, H., Yamanaka, T., Masuda, N., Ohno, S., Nakamura, S., Nakayama, T., Kashiwaba, M., Kamigaki, S. and Kuroi, K., (2010) Clinical significance of the 21-gene signature (oncotype DX) in hormone receptor-positive early stage primary breast cancer in the Japanese population. Cancer, 116, 3112–3118

[63] Feng, X., Xu, X., Li, D., Cui, Q. and Wang, E. (2019) Germline genomic patterns are associated with cancer risk, oncogenic pathways and clinical outcomes. bioRxiv, 616268

[64] Xu, X., Li, J., Zou, J., Feng, X., Zhang, C., Zheng, R., Duanmu, W., Saha-Mandal, A., Ming, Z. and Wang, E. (2019) Association of germline variants in natural killer cells with tumor immune microenvironment subtypes, tumor-infiltrating lymphocytes, immunotherapy response, clinical outcomes, and cancer risk. JAMA Netw. Open, 2, e199292

[65] Sharma, S., Kelly, T. K. and Jones, P. A. (2010) Epigenetics in cancer. Carcinogenesis, 31, 27–36

[66] Witkowski, L., Carrot-Zhang, J., Albrecht, S., Fahiminiya, S., Hamel, N., Tomiak, E., Grynspan, D., Saloustros, E., Nadaf, J., Rivera, B., (2014) Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat. Genet., 46, 438–443

[67] Butler, J. S., Koutelou, E., Schibler, A. C. and Dent, S. Y. R. (2012) Histone-modifying enzymes: regulators of developmental decisions and drivers of human disease. Epigenomics, 4, 163–177

[68] Klutstein, M., Nejman, D., Greenfield, R. and Cedar, H. (2016) DNA methylation in cancer and aging. Cancer Res., 76, 3446–3450

[69] Miao, D., Margolis, C. A., Gao, W., Voss, M. H., Li, W., Martini, D. J., Norton, C., Bossé, D., Wankowicz, S. M., Cullen, D., (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science, 359, 801–806

[70] Pan, D., Kobayashi, A., Jiang, P., Ferrari de Andrade, L., Tay, R. E., Luoma, A. M., Tsoucas, D., Qiu, X., Lim, K., Rao, P., (2018) A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science, 359, 770–775

[71] Kearney, C. J., Vervoort, S. J., Hogg, S. J., Ramsbottom, K. M., Freeman, A. J., Lalaoui, N., Pijpers, L., Michie, J., Brown, K. K., Knight, D. A., (2018) Tumor immune evasion arises through loss of TNF sensitivity. Sci. Immunol., 3, eaar3451

[72] Beatty, G. L. and Paterson, Y. (2000) IFN-γ can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen. J. Immunol., 165, 5502–5508

[73] Houlahan, K. E., Shiah, Y.-J., Gusev, A., Yuan, J., Ahmed, M., Shetty, A., Ramanand, S. G., Yao, C. Q., Bell, C., O’Connor, E., (2019) Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nat. Med., 25, 1615–1626

[74] Foulkes, W. D. (2008) Inherited susceptibility to common cancers. N. Engl. J. Med., 359, 2143–2153

[75] Torgovnick, A. and Schumacher, B. (2015) DNA repair mechanisms in cancer development and therapy. Front. Genet., 6, 157

[76] Büttner, R., Longshore, J. W., López-Ríos, F., Merkelbach-Bruse, S., Normanno, N., Rouleau, E. and Penault-Llorca, F. (2019) Implementing TMB measurement in clinical practice: considerations on assay requirements. ESMO Open, 4, e000442

[77] Caruso, C. (2019) TMB faces validation hurdles. Cancer Discov., 9, 1334–1334

[78] Potapova, T. A., Zhu, J. and Li, R. (2013) Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos. Cancer Metastasis Rev., 32, 377–389

[79] Pérez de Castro, I. and Malumbres, M. (2012) Mitotic stress and chromosomal instability in cancer: the case for TPX2. Genes Cancer, 3, 721–730

[80] Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., (2017) cGAS surveillance of micronuclei links genome instability to innate immunity. Nature, 548, 461–465

[81] Motwani, M. and Fitzgerald, K. A. (2017) cGAS micro-manages genotoxic stress. Immunity, 47, 616–617

[82] Breunis, W. B., Tarazona-Santos, E., Chen, R., Kiley, M., Rosenberg, S. A. and Chanock, S. J. (2008) Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J. Immunother., 31, 586–590

[83] Hamid, O., Schmidt, H., Nissan, A., Ridolfi, L., Aamdal, S., Hansson, J., Guida, M., Hyams, D. M., Gómez, H., Bastholt, L., (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med., 9, 204

[84] Kuehn H. S., Ouyang W., Lo B., Deenick E. K., Niemela J. E., Avery D. T., Schickel J.-N., Tran D. Q., Stoddard J., Zhang Y., (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science, 345,1623–1627

[85] Chat, V., Ferguson, R., Simpson, D., Kazlow, E., Lax, R., Moran, U., Wilson, M., Pavlick, A. C., Sullivan, R. J., Flaherty, K., (2018) Autoimmune genetic variants as germline biomarkers of response in melanoma immunotherapy treatment. J. Clin. Oncol., 36, 3079–3079

[86] Ugurel, S., Schrama, D., Keller, G., Schadendorf, D., Bröcker, E.-B., Houben, R., Zapatka, M., Fink, W., Kaufman, H. L. and Becker, J. C. (2008) Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol. Immunother., 57, 685–691

[87] Uccellini, L., De Giorgi, V., Zhao, Y., Tumaini, B., Erdenebileg, N., Dudley, M. E., Tomei, S., Bedognetti, D., Ascierto, M. L., Liu, Q., (2012) IRF5 gene polymorphisms in melanoma. J. Transl. Med., 10, 170

[88] Arce Vargas, F., Furness, A. J. S., Litchfield, K., Joshi, K., Rosenthal, R., Ghorani, E., Solomon, I., Lesko, M. H., Ruef, N., Roddie, C., (2018) Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell, 33, 649–663.e4

[89] Van Allen, E. M., Golay, H. G., Liu, Y., Koyama, S., Wong, K., Taylor-Weiner, A., Giannakis, M., Harden, M., Rojas-Rudilla, V., Chevalier, A., (2015) Long-term benefit of PD-L1 blockade in lung cancer associated with JAK3 activation. Cancer Immunol. Res., 3, 855–863

[90] Zitvogel, L., Kepp, O. and Kroemer, G. (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat. Rev. Clin. Oncol., 8, 151–160

[91] Vacchelli E., Ma Y., Baracco E. E., Sistigu A., Enot D. P., Pietrocola F., Yang H., Adjemian S., Chaba K., Semeraro M., (2015) Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science, 350, 972–978

[92] Lamichhane, P., Karyampudi, L., Shreeder, B., Krempski, J., Bahr, D., Daum, J., Kalli, K. R., Goode, E. L., Block, M. S., Cannon, M. J., (2017) IL10 Release upon PD-1 blockade sustains immunosuppression in ovarian cancer. Cancer Res., 77, 6667–6678

[93] Zaretsky, J. M., Garcia-Diaz, A., Shin, D. S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D. Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., (2016) Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med., 375, 819–829

[94] Gao, J., Shi, L. Z., Zhao, H., Chen, J., Xiong, L., He, Q., Chen, T., Roszik, J., Bernatchez, C., Woodman, S. E., (2016) Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell, 167, 397–404.e9

[95] Shan, J., Chouchane, A., Mokrab, Y., Saad, M., Boujassoum, S., Sayaman, R. W., Ziv, E., Bouaouina, N., Remadi, Y., Gabbouj, S., (2019) Genetic variation in CCL5 signaling genes and triple negative breast cancer: susceptibility and prognosis implications. Front. Oncol., 9, 1328

[96] Hosseini, E., Schwarer, A. P. and Ghasemzadeh, M. (2015) Do human leukocyte antigen E polymorphisms influence graft-versus-leukemia after allogeneic hematopoietic stem cell transplantation? Exp. Hematol., 43, 149–157

[97] Wu, S., Powers, S., Zhu, W. and Hannun, Y. A. (2016) Substantial contribution of extrinsic risk factors to cancer development. Nature, 529, 43–47

[98] Tomasetti, C., Li, L. and Vogelstein, B. (2017) Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science, 355, 1330–1334

COMPLIANCE WITH ETHICS GUIDELINES

The authors Xue Jiang, Mohammad Asad, Lin Li, Zhanpeng Sun, Jean-Sébastien Milanese, Bo Liao and Edwin Wang declare that they have no conflict of interests.

This article is a review article and does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2020 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature