Molecular Basis of Overcoming Immune Checkpoint Inhibitor Resistance by Targeting Myeloid Derived Suppressor Cells

Abstract

In the last decades, new strategies such as Immune Checkpoint Inhibitor (ICI) therapy have increased survival chances for cancer patients considerably and have become one of the leading immunotherapies to combat cancer. Immune Checkpoint Proteins are expressed to maintain immune homeostasis and prevent autoimmune disease. Using ICI therapy, activation of cytotoxic T cells is promoted with monoclonal antibodies. However, responses to ICI therapy are highly dependent upon the (immunosuppressive) tumor microenvironment (TME). One of the major drivers in creating this immunosuppressive environment are Myeloid Derived Suppressor Cells (MDSCs). MDSCs are a heterogenous population of immature myeloid cells that inhibit T cell proliferation, differentiation and activation. Thereby, MDSCs play a major role in the development of resistance to ICI therapy. In this paper, we review different MDSC targeting strategies, such as depletion, inhibition of immunosuppressive characteristics, and promoting maturation. Furthermore, we assess the potential to overcome ICI resistance by combining ICI therapy with targeting of MDSCs. Studies combining FDA approved anti-CTLA-4, anti-PD-1, and anti-PD-L1 ICI therapies in combination with MDSC targets show reduced MDSC levels and enhances cytotoxic T cell infiltration in the TME of preclinical mouse models, as well as in clinical trials. Therefore, we conclude that targeting important molecular pathways in MDSCs can be used to overcome ICI resistance. However, since the TME is unique for every tumor, more research into molecular pathways is necessary to pave the way towards personalized medicine.