DNA damage, tumor mutational load and their impact on immune responses against cancer


Liontos M, Anastasiou I, Bamias A, Dimopoulos M-A. DNA damage, tumor mutational load and their impact on immune responses against cancer. Annals of Translational Medicine [Internet]. 2016;4(14).


Advances in immunotherapy have changed the therapeutic landscape in many malignancies. Immune checkpoint inhibitors have already received regulatory approval in melanomas, lung, renal and bladder carcinomas. A common feature of these neoplasms is the increased mutational load, related to a possible increase number of tumor neoantigens that are recognized by the immune system. The mechanisms that DNA damage could confer to the mutational load and the formation of neoantigens and how this could be exploited to advance our immunotherapeutic strategies is discussed in this review. © Annals of Translational Medicine.


Cited By :1Export Date: 18 February 2017References: Borghaei, H., Paz-Ares, L., Horn, L., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer (2015) N Engl J Med, 373, pp. 1627-1639;Brahmer, J., Reckamp, K.L., Baas, P., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer (2015) N Engl J Med, 373, pp. 123-135; Garon, E.B., Rizvi, N.A., Hui, R., Pembrolizumab for the treatment of non-small-cell lung cancer (2015) N Engl J Med, 372, pp. 2018-2028; Hodi, F.S., O'Day, S.J., McDermott, D.F., Improved survival with ipilimumab in patients with metastatic melanoma (2010) N Engl J Med, 363, pp. 711-723; Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma (2015) N Engl J Med, 373, pp. 23-34; Motzer, R.J., Escudier, B., McDermott, D.F., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma (2015) N Engl J Med, 373, pp. 1803-1813; Robert, C., Schachter, J., Long, G.V., Pembrolizumab versus Ipilimumab in Advanced Melanoma (2015) N Engl J Med, 372, pp. 2521-2532; Schumacher, T.N., Schreiber, R.D., Neoantigens in cancer immunotherapy (2015) Science, 348, pp. 69-74; Le, D.T., Uram, J.N., Wang, H., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency (2015) N Engl J Med, 372, pp. 2509-2520; Alexandrov, L.B., Nik-Zainal, S., Wedge, D.C., Signatures of mutational processes in human cancer (2013) Nature, 500, pp. 415-421; Branzei, D., Foiani, M., Regulation of DNA repair throughout the cell cycle (2008) Nat Rev Mol Cell Biol, 9, pp. 297-308; Bartkova, J., Rezaei, N., Liontos, M., Oncogeneinduced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints (2006) Nature, 444, pp. 633-637; Halazonetis, T.D., Gorgoulis, V.G., Bartek, J., An oncogeneinduced DNA damage model for cancer development (2008) Science, 319, pp. 1352-1355; Jackson, S.P., Bartek, J., The DNA-damage response in human biology and disease (2009) Nature, 461, pp. 1071-1078; Gorgoulis, V.G., Vassiliou, L.V., Karakaidos, P., Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions (2005) Nature, 434, pp. 907-913; Stratton, M.R., Campbell, P.J., Futreal, P.A., The cancer genome (2009) Nature, 458, pp. 719-724; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation (2011) Cell, 144, pp. 646-674; Hanahan, D., Weinberg, R.A., The hallmarks of cancer (2000) Cell, 100, pp. 57-70; Gasser, S., Orsulic, S., Brown, E.J., The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor (2005) Nature, 436, pp. 1186-1190; Ardolino, M., Zingoni, A., Cerboni, C., DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction (2011) Blood, 117, pp. 4778-4786; Groh, V., Bahram, S., Bauer, S., Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium (1996) Proc Natl Acad Sci U S A, 93, pp. 12445-12450; Cerboni, C., Fionda, C., Soriani, A., The DNA Damage Response: A Common Pathway in the Regulation of NKG2D and DNAM-1 Ligand Expression in Normal, Infected, and Cancer Cells (2014) Front Immunol, 4, p. 508; Vivier, E., Tomasello, E., Paul, P., Lymphocyte activation via NKG2D: towards a new paradigm in immune recogniton? (2002) Curr Opin Immunol, 14, pp. 306-311; Bauer, S., Groh, V., Wu, J., Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA (1999) Science, 285, pp. 727-729; Diefenbach, A., Jensen, E.R., Jamieson, A.M., Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity (2001) Nature, 413, pp. 165-171; Guerra, N., Tan, Y.X., Joncker, N.T., NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy (2008) Immunity, 28, pp. 571-580; Bartkova, J., Horejsí, Z., Koed, K., DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis (2005) Nature, 434, pp. 864-870; Liu, G., Lu, S., Wang, X., Perturbation of NK cell peripheral homeostasis accelerates prostate carcinoma metastasis (2013) J Clin Invest, 123, pp. 4410-4422; Miyamoto, S., Nuclear initiated NF-κB signaling: NEMO and ATM take center stage (2011) Cell Res, 21, pp. 116-130; McCool, K.W., Miyamoto, S., DNA damage-dependent NF-κB activation: NEMO turns nuclear signaling inside out (2012) Immunol Rev, 246, pp. 311-326; Rodier, F., Coppé, J.P., Patil, C.K., Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion (2009) Nat Cell Biol, 11, pp. 973-979; Gorgoulis, V.G., Halazonetis, T.D., Oncogene-induced senescence: the bright and dark side of the response (2010) Curr Opin Cell Biol, 22, pp. 816-827; Di Micco, R., Sulli, G., Dobreva, M., Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer (2011) Nat Cell Biol, 13, pp. 292-302; Linnemann, C., van Buuren, M.M., Bies, L., Highthroughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma (2015) Nat Med, 21, pp. 81-85; Matsushita, H., Vesely, M.D., Koboldt, D.C., Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting (2012) Nature, 482, pp. 400-404; van Rooij, N., van Buuren, M.M., Philips, D., Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma (2013) J Clin Oncol, 31, pp. e439-e442; Gubin, M.M., Zhang, X., Schuster, H., Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens (2014) Nature, 515, pp. 577-581; Haraldsdottir, S., Hampel, H., Tomsic, J., Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations (2014) Gastroenterology, 147, pp. 1308-1316.e1; Van Allen, E.M., Miao, D., Schilling, B., Genomic correlates of response to CTLA-4 blockade in metastatic melanoma (2015) Science, 350, pp. 207-211; Rizvi, N.A., Hellmann, M.D., Snyder, A., Cancer immunology (2015) Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 348, pp. 124-128; Rooney, M.S., Shukla, S.A., Wu, C.J., Molecular and genetic properties of tumors associated with local immune cytolytic activity (2015) Cell, 160, pp. 48-61; Snyder, A., Makarov, V., Merghoub, T., Genetic basis for clinical response to CTLA-4 blockade in melanoma (2014) N Engl J Med, 371, pp. 2189-2199