Genomics Role in Cancer Immunosurveillance: Impact on Immunotherapy Response

Context: One of the most important achievements in cancer research is the development of cancer immunotherapy. However, only a subset of patients respond to immunotherapy modalities, and few patients respond for a durable time. Here, we review the possible genomic mechanisms of response and resistance to these therapies, which can lead to the selection of responders, who may benefit most from immunotherapy. Evidence Acquisition: We searched PubMed, Scopus, and Web of Science Core Collection with the following keywords: “Immunotherapy, Resistance, Response, Programmed cell death 1 receptor, CTLA-4, Cancer immunity, Tumor Genomics, and Somatic Mutations”. Results: T cells that specifically recognize cancer-associated antigens, are responsible for the immune system response against cancer. Nonsynonymous mutations, which are transcribed and translated into polypeptides,maygeneratenewepitopes (neoepitopes), which can lead to their presentation on major histocompatibility (MHC) class I molecules and subsequently recognized by the adaptive immune system. Despite the unprecedented durable responses, the majority of patients treated with cancer immunotherapies do not respond to the therapy (primary resistance), and some patients relapse after an initial response (acquired resistance). Resistance to immunotherapy can be a result of tumor cell intrinsic or extrinsic factors. There is correlation between tumor mutation burden (TMB) and response to immunotherapy. In addition, mismatch repair deficient tumors harbor considerably more somatic mutations compared to mismatch repair proficient tumors and respond better to anti-programmed cell death protein 1 (anti-PD1) therapy. Mutations in other DNA repair genes may also affect immunotherapy response. Conclusions: Neoantigen specific T cells constitute a major “active component” for the success of cancer immunotherapies. The genetic damage that confers tumorigenic growth, can also be targeted by the immune machinery to inhibit cancer development and progression. With further validation of experiments, genomics-based approaches can allow to select patients most likely to achieve durable responses to immunotherapy modalities.