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.

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

“…As PD-1 is often present on activated and tumour-infiltrating γδ T cells, the presence of PD-L1 in the TME and expressed on tumour cells can limit γδ T-cell anti-tumour activity [ 188 , 191 , 192 ] ( Figure 3 ). Therefore, checkpoint inhibitor immunotherapy is being explored to enhance the anti-tumour function of γδ T cells [ 191 , 193 , 194 , 195 ]. For example, as a strategy to boost the anti-tumour activity of Vγ9Vδ2 T cells, the use of PD-1 blockade in conjunction with PAg stimulation has been employed [ 196 , 197 ], aiming to neutralise the effect of the PAg stimulation-related upregulation of PD-1 on γδ T cells [ 198 ].…”

In Acute Dengue Infection, High TIM-3 Expression May Contribute to the Impairment of IFNγ Production by Circulating Vδ2 T Cells

“…A similar inhibitory function was also exerted by TIM-3 which is up-regulated both on αβ and γδ T cells after activation [38,39]. Several observations demonstrated a role of both PD-1 and TIM-3 in reducing cytokine production and cytotoxicity of γδ T cells both in viral infection and in cancer [40].…”

PD-1/PD-L1 immune-checkpoint blockade induces immune effector cell modulation in metastatic non-small cell lung cancer patients: A single-cell flow cytometry approach

“…NKT cells are cells at the “bridge” between innate and adaptive immune response, whose activation depends upon the engagement of their T-cell receptor (TCR) by the major histocompatibility complex (MHC)-like CD1d loaded with lipids, given that, once activated, these cells could produce various cytokines, such as interferon (IFN)γ, interleukin (IL)4, IL2, IL10, and IL21, and reprogram dendritic cells to produce IL12. It is conceivable that (as reported in multiple preclinical and clinical models of cancer immunotherapy, including melanoma) the treatment with immune-checkpoint inhibitors could activate NKT cells, which in turn rescue tumor-specific CTLs from exhaustion ( 29 , 30 ). These data are consistent with our results showing that NKT increase was associated with a trend to improved survival, further supporting the idea of a broader microenvironmental immune re-modeling impacting patient outcomes.…”