New approach in Understanding Colorectal Cancer Immunosuppression and Immunotherapy-Based Strategies in the Treatment of Microsatellite Stable Colorectal Cancer

Abstract Except the widely accepted use of immune Checkpoint inhibitors in the treatment of microsatellite instability-high (MSI-H) mismatch repair-deficient (MMRd) CRCs representing about 5% of all metastatic (m)CRC patients, new strategies are applied to cure MMR-proficient (MMRp) mCRC patients. Tumor microenvironment (TME) is decisive for cancer development. The determination of some immunoeffective and immunosuppressive immune cells and some cytokines, chemokines and growth factors in the TME gives Information about the use of immune Checkpoint inhibitors in MMRp CRCs. The increased level of IL-6 in the serum and increased number of IL-6+ immune cells in TME, the increased number of IL-17+ Th17 cells, and of FoxP3+ cells are used to determine the use of anti-IL-6 antibody and of anti-FoxP3 antibody for treatment. The determination of high CD8+, high PD-1 expression and little or no Th17 cells appoint better response to anti-PD-1 therapy. The used combination therapies are: combination of immunotherapy with chemotherapy, with radiation therapy, with targeted therapy, with vaccines, oncolytic viruses and bispeeifie antibodies. Classical treatment of CRC patients has included chemotherapy, radiotherapy and surgery. Recently, immunotherapy has been added as a mainstay for therapy of CRC. The main checkpoint inhibitors used in CRC immunotherapy are pembrolizumab and nivolumab (anti-PD-1), durvalumab (anti-PD-L1), ipilimumab (anti-CTLA-4), favezelimab (anti-LAG3), etc. They are applied after fluorapyrimidine, oxaliplain, and irinotecan therapy. In conclusion, we may state that the future treatment of MSS CRC is in combination therapies, i.e. conventional and immunotherapies. We consider that immune infiltrate in TME must be assessed in order to determine combination therapies.