A review of mechanisms of resistance to immune checkpoint inhibitors and potential strategies for therapy

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer over the last decade, bringing about a paradigm shift in systemic cancer therapy away from traditional cytotoxic and targeted therapies. While some patients have dramatic treatment responses, it is sobering to note that most tumors are either resistant at the outset, or develop resistance after initial response. A major area of translational and clinical research is in identifying therapeutic strategies to overcome resistance to ICIs. We have performed an in-depth review of the different mechanisms of resistance and potential avenues to overcome resistance through rationally designed combination treatment with ICIs.

Keywords: CTLA-4; Immunotherapy resistance; PD-1; PD-L1; tumor microenvironment.

Figure 1

Steps involved in the generation of an effective tumor-directed T cell response through the formation of tumor reactive T cells, the activation of effector T cell function and the formation of effector memory T cells (A); resistance to immune checkpoint inhibitors may occur due to multiple different factors within the tumor cell or the tumor microenvironment (B). MHC: major histocompatibility complex; PD-1: programmed death 1; PD-L1: programmed cell death ligand 1; MDSC: myeloid-derived suppressor cell; IDO: Indoleamine 2,3-dioxygenase; APC: antigen-presenting cell

Figure 2

Mechanisms that may either alone, or in combination lead to de novo or acquired resistance to immune checkpoint inhibition (A); Primary and acquired mechanisms of resistance at different points in the cancer immunity cycle and potential therapeutic strategies to overcome them (B). PD-1: programmed death 1; PD-L1: programmed cell death ligand 1; IDO: Indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor