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

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.

Keywords: MAIT cells; NKT cells; cancer; immune checkpoint receptors; immunotherapy; γδ T cells.

Figure 1

Balance between T cell activation and T cell inhibition. (A) Under normal conditions, the inhibitory signals mediated by ICR ligation down-regulate T cell responses to prevent immunopathology and autoimmunity. (B) During chronic inflammation, T cells are overwhelmed by several activation signals, overcoming ICR inhibition and tipping the balance towards constitutive T cell activation. (C) Despite the presence of antigen, in chronic viral infection and cancer, the immunosuppressive factors in the microenvironment break the equilibrium towards chronic T cell inhibition or exhaustion. APC: antigen-presenting cell; ICR: immune checkpoint receptor; ICR−L: immune checkpoint receptor ligand.

Figure 2

Checkpoint inhibition therapy. (A) ICR signaling in the tumor microenvironment inhibits T cell responses, thus contributing to tumor immune escape; CPI administration blocks ICR/ICR−L interactions, restoring T cell antitumor responses. (B) ICR-mediated inhibition of IL−17-producing T cells blocks their pro-tumor activity; CPI therapy targeting these cells will promote tumor growth. CPI: checkpoint inhibitor; ICR: immune checkpoint receptor; ICR−L: immune checkpoint receptor ligand; IL−17: interleukin 17; TCR: T cell receptor.

Figure 3

Potential importance of unconventional T cells during CPI therapy. Targeting γδ T cells, MAIT cells and NKT cells with CPI therapy may lead to strong MHC-independent anti-tumor responses. However, this treatment could also trigger the production of pro-inflammatory cytokines that promote tumor growth. In addition, unconventional T cell responses might contribute to the side effects often seen during CPI therapy. Abbreviations as in text.