A Highlight of the Mechanisms of Immune Checkpoint Blocker Resistance

Abstract

In recent years, as our understanding of tumor immunology is continuously improved, immunotherapy has come to the center stage of cancer therapy and is deemed as the most promising approach for cancer control. Although immunotherapy, particularly immune checkpoint blockade (ICB), has achieved a milestone in several types of tumors, the majority of cancer patients do not benefit from immunotherapy. The dismal outcome of cancer immunotherapy is mainly due to primary or acquired resistance arising from tumor immune evasion. Exploring the mechanisms of tumor immune evasion in the course of immunotherapy may identify biological targets to conquer tumor resistance to immunotherapy. In this review, we highlight tumor cell-intrinsic and -extrinsic factors that may underlie tumor resistance to immune checkpoint blockers. Targeting these factors in combination with immune checkpoint blockers points to the future direction of cancer immunotherapy.

Keywords: ICB; PD-1; anti-PD-1; immune microenvironment; immunotherapy resistance.

FIGURE 1

Summary of drug resistance in tumor immunotherapy. The mechanisms of drug resistance and immune escape in tumor immunotherapy include tumor cell-internal and -external factors. The internal factors include loss of tumor antigens and intratumor heterogeneity, defects in antigen presentation, abnormal oncogenic signaling and IFN-γ signal pathway, innate anti-PD-1 resistance signature, increased expression of constitutive PD-L1, epigenetic changes, and lack or exhaustion of T cells. The external factors include immunosuppressive cells and cytokines in tumor microenvironment, tumor metabolites in immune microenvironment, new immune checkpoints, and intestinal microflora. PD-1, programmed death 1; PD-L1, programmed death ligand 1; Anti, Anti-PD1/anti-PDL1; HLA, human leukocyte antigen; TCR, T-cell receptor; IFN-γ, interferon-γ; IFN-γR, Interferon-γ receptor; Treg, regulatory T cell; Neuropilin-1, neurociliary protein 1; TAM, tumor associated macrophage; CSF-1, macrophage colony stimulating factor; MDSC, myelogenous suppressor cell; IL-6, interleukin-6; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor.