Mechanisms of resistance to immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.

Keywords: T cell; cancer immunology; exhaustion; immune checkpoint inhibitor; resistance.

FIGURE 1

Process of T‐cell activation and main mechanisms of resistance to immune checkpoint inhibitors (ICIs). The seven steps of T‐cell activation that lead to killing cancer cells and the three main mechanisms of resistance to ICIs related to this process are summarized. APC, antigen‐presenting cell; MHC, major histocompatibility complex; TME, tumor microenvironment. This figure was created with BioRender.com

FIGURE 2

Multiple costimulatory and inhibitory interactions regulate T‐cell responses. Representative coinhibitory and costimulatory immune checkpoint molecules and their ligands are presented. 4‐1BBL, 4‐1BB ligand; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; GAL‐9, galectin 9; GITR, glucocorticoid‐induced tumor necrosis factor receptor; GITR‐L, GITR ligand; ICOS, inducible T‐cell costimulator; ICOSL, ICOS ligand; LAG‐3, lymphocyte activation gene 3; OX40L, OX40 ligand; PD‐1, programmed cell death 1; PD‐L1/2, PD‐ligand 1/2; TIGIT, T‐cell immunoreceptor with immunoglobulin and ITIM domains; TIM‐3, T‐cell membrane protein 3. This figure was created with BioRender.com

FIGURE 3

The progressive process of T‐cell exhaustion. Among exhausted T cells, PD‐1^lowCXCR5⁺TCF1⁺ progenitor‐exhausted T cells are expected to be reactivated by anti‐PD‐1/PD‐L1 mAbs. In contrast, PD‐1^highCXCR5⁻TCF1⁻ terminally differentiated exhausted T cells are considered dysfunctional and incapable of being reactivated. LAG‐3, lymphocyte activation gene 3; PD‐1, programmed cell death 1; TCF‐1, T‐cell factor 1; TIM‐3, T‐cell membrane protein 3. This figure was created with BioRender.com