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.

Early-life cues shape the immune system during adulthood. However, early-life signaling pathways and their temporal functions are not well understood. Herein, we demonstrate that the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2), which are E3 ubiquitin ligases, sustain interleukin (IL)-17–producing γ δ T cells (γδT17) and group 3 innate lymphoid cells (ILC3) during late neonatal and prepubescent life. We show that cell-intrinsic deficiency of cIAP1/2 at 3–4 wk of life leads to downregulation of the transcription factors cMAF and RORγt and failure to enter the cell cycle, followed by progressive loss of γδT17 cells and ILC3 during aging. Mice deficient in cIAP1/2 have severely reduced γδT17 cells and ILC3, present with suboptimal γδT17 responses in the skin, lack intestinal isolated lymphoid follicles, and cannot control intestinal bacterial infection. Mechanistically, these effects appear to be dependent on overt activation of the non-canonical NF-κB pathway. Our data identify cIAP1/2 as early-life molecular switches that establish effective type 3 immunity during aging.

AbstractRORγt+ γδ T cells, known as γδT17, are an innate-like subset of T cells that produce interleukin (IL)-17A and initiate type 3 immune responses during infections or autoimmune pathologies. Herein we show that the cellular inhibitor of apoptosis proteins cIAP1 and 2 are required for the peripheral homeostasis of γδT17 but not for their thymic development. γδT17 cells that were deficient in both cIAP1 and 2 were profoundly reduced in the peripheral lymph nodes and skin. Likewise, both RORγt+ innate lymphoid cells (ILC3) and RORγt+ Tbet+ γδ T cells were reduced in the lamina propria of adult mice. Further, cIAP1 and 2 were required for the expression of the transcription factors RORγt and cMAF in γδT17 cells during neonatal and adult life. Single deficiency of either cIAP1 or 2 did not affect the homeostasis or transcription factor profile of γδT17 cells. Moreover, bone marrow reconstitutions and transfer of neonatal γδ T cells to RAG1−/− hosts showed that both intrinsic and extrinsic factors contribute to the loss of γδT17 cells in cIAP1/2 double deficient mice, while only extrinsic signals were responsible for the decrease of ILC3 cells. Deficiency of γδT17 cells in cIAP1 and cIAP2 double deficient animals, or the presence of functionally defective γδT17 cells did not confer protection against IMQ-induced psoriasis. Collectively, our data reveal a previously undescribed role for cIAP1 and cIAP2 in the homeostasis of γδT17 and ILC3 cells.

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