Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

SIMPLE SUMMARY: All conventional major histocompatibility complex (MHC)-restricted T cells transiently express immune checkpoint/inhibitory receptors (ICRs) following activation as a means to counter-regulate overactivation. However, tumors promote chronic ICR expression rendering T cells chronically unresponsive or “exhausted”. Checkpoint inhibitor (CPI) therapy targets and blocks ICRs, restoring T cell activation and anti-tumor immunity. However, CPI therapy often fails, partly because of the tumor’s many abilities to inhibit MHC-driven T cell responses. In this regard, our immune system contains an arsenal of unconventional non-MHC-restricted T cells, whose importance in anti-tumor immunity is rapidly gaining momentum. There is currently little knowledge as to whether unconventional T cells can get exhausted and how CPI therapy affects them. In this article we review the current understanding of the role of ICRs in unconventional T cell biology and discuss the importance of targeting these unique immune cell populations for CPI therapy. ABSTRACT: In recent years, checkpoint inhibitor (CPI) therapy has shown promising clinical responses across a broad range of cancers. However, many patients remain unresponsive and there is need for improvement. CPI therapy relies on antibody-mediated neutralization of immune inhibitory or checkpoint receptors (ICRs) that constitutively suppress leukocytes. In this regard, the clinical outcome of CPI therapy has primarily been attributed to modulating classical MHC-restricted αβ T cell responses, yet, it will inevitably target most lymphoid (and many myeloid) populations. As such, unconventional non-MHC-restricted gamma delta (γδ) T, mucosal associated invariant T (MAIT) and natural killer T (NKT) cells express ICRs at steady-state and after activation and may thus be affected by CPI therapies. To which extent, however, remains unclear. These unconventional T cells are polyfunctional innate-like lymphocytes that play a key role in tumor immune surveillance and have a plethora of protective and pathogenic immune responses. The robust anti-tumor potential of γδ T, MAIT, and NKT cells has been established in a variety of preclinical cancer models and in clinical reports. In contrast, recent studies have documented a pro-tumor effect of innate-like T cell subsets that secrete pro-inflammatory cytokines. Consequently, understanding the mechanisms that regulate such T cells and their response to CPI is critical in designing effective cancer immunotherapies that favor anti-tumor immunity. In this Review, we will discuss the current understanding regarding the role of immune checkpoint regulation in γδ T, MAIT, and NKT cells and its importance in anti-cancer immunity.