Mechanisms of Intrinsic Tumor Resistance to Immunotherapy

Abstract

An increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO) overexpression, loss of phosphatase and tensin homologue (PTEN) expression, and overexpression of the Wnt⁻β-catenin pathway. Current work in immunotherapy continues to identify various tumor resistance mechanisms; future work is needed to develop adjuvant treatments that target those mechanisms, in order to improve the efficacy of immunotherapy and to expand its scope.

Keywords: cancer immunotherapy; oncogenes; resistance; signaling pathways.

Figure 1

Simplified depiction of CD8⁺ T-cell antitumor immunity. CD8⁺ T cells are sensitized by dendritic cells via interactions between TCRs and antigen-bearing MHC I receptors, causing activation and proliferation of the CD8⁺ T cells. Then, CD8⁺ T cells migrate from the lymph node to the tumor site, targeting the antigen-bearing tumor cells for apoptosis via perforin and granzymes. The tumor cell releases antigens, which are captured by dendritic cells, which mature in the lymph nodes and cause further potentiation of T cells. Ag = antigen; MHC = major histocompatibility complex; TCR = T-cell antigen receptor.