Immunotherapy for colorectal cancer

Abstract

Progress in understanding complex interactions between cancer cells and the immune system has led to the development of new methods of treatment — immunotherapy, modulating the anti-cancer response of the immune system. For several years, colorectal cancer (CRC) was thought to be a cancer with low immune stimulation potential, but in recent years the favorable prognostic value of lymphocytic infiltrates in the tumor has been noted. Currently it is well known that the stimulation of the immune system by CRC cells is associated with the accumulation of mutations in DNA microsatellites. This phenomenon results from impairment of function of genes (mainly MLH1, MSH2, MSH6 and PMS2) encoding proteins involved in correction of mismatched nucleotides during replication (dMMR), whose phenotypic reflection is microsatellite instability (MSI). It affects about 15–20% of CRC, with clear differences depending on the stage of cancer — about 20% in stage II, 12% in stage III, and only around 4% in stage IV. dMMR/MSI cancers are highly immunogenic through overexpression of tumor antigens and can induce a deep immune response. Cancers with intact repair gene system (pMMR) and stable microsatellites (MSS) show poor immunogenicity, which makes it difficult to induce an anti-tumor immune response. The relationship between impairment of the mismatch repair system and the induction of an anti-cancer immune response justifies the use of checkpoint inhibitors of this response in the treatment of patients with CRC MSI/dMMR. In MSS/pMMR cancers, checkpoint inhibitors used in monotherapy are not effective. However, studies are underway to combine these drugs with other methods of systemic treatment (chemotherapy, EGFR inhibitors, angiogenesis inhibitors, MET inhibitors), as well as radiotherapy.