Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

Abstract

The differentiation, survival, and effector function of tumor-specific CD8⁺ cytotoxic T cells lie at the center of antitumor immunity. Due to the lack of proper costimulation and the abundant immunosuppressive mechanisms, tumor-specific T cells show a lack of persistence and exhausted and dysfunctional phenotypes. Multiple coinhibitory receptors, such as PD-1, CTLA-4, VISTA, TIGIT, TIM-3, and LAG-3, contribute to dysfunctional CTLs and failed antitumor immunity. These coinhibitory receptors are collectively called immune checkpoint receptors (ICRs). Immune checkpoint inhibitors (ICIs) targeting these ICRs have become the cornerstone for cancer immunotherapy as they have established new clinical paradigms for an expanding range of previously untreatable cancers. Given the nonredundant yet convergent molecular pathways mediated by various ICRs, combinatorial immunotherapies are being tested to bring synergistic benefits to patients. In this review, we summarize the mechanisms of several emerging ICRs, including VISTA, TIGIT, TIM-3, and LAG-3, and the preclinical and clinical data supporting combinatorial strategies to improve existing ICI therapies.

Keywords: CTLA-4; LAG3; PD-1; TIGIT; TIM3; VISTA; combinatorial immunotherapies; immune checkpoint inhibitors.

Figure 1

Overview of coinhibitory ICRs and their effects in conventional T cells. T-cell activation requires TCR recognition of cognate antigens presented on APCs and costimulation provided by B7/CD28 or CD115/CD226 interactions. On the other hand, many coinhibitory ligand/receptor pathways are activated to dampen T-cell responses. The B7/CTLA-4 and PD-L1/2/PD-1 pathways are the cornerstones of the immune checkpoint paradigm. Emerging inhibitory ICRs, including TIGIT, LAG-3, TIM-3, and VISTA, each recognized by multiple ligands, play nonredundant yet convergent roles as the “brakes” of T-cell responses.

Figure 2

The signaling effects of ICRs in antigen-presenting cells. Aside from suppressing T-cell activation, many ICRs regulate the maturation, antigen presentation, cytokine production, and other effector functions of DCs and tumor-associated macrophages. CTLA-4 reduces the surface expression of B7 molecules through trans-endocytosis. LAG-3 and TIGIT trigger signaling in a reverse direction by engaging their respective binding partners MHCII and CD155. On the other hand, PD-1, TIM-3, and VISTA are expressed in APCs and transmit inhibitory signals to inhibit the effector functions of APCs, including phagocytosis, antigen presentation, and cytokine production. Both PD-1 and VISTA are also expressed in tumor-driven MDSCs and contribute to the differentiation and suppressive function of MDSCs.