γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer

Abstract

The potential of cancer immunotherapy relies on the mobilization of immune cells capable of producing anti-tumour cytokines and effectively killing tumour cells. These are major attributes of  T cells, a lymphoid lineage that is often underestimated despite its major role in tumour immune surveillance, which has been established in a variety of pre-clinical cancer models. This notwithstanding, in particular instances the tumour microenvironment seemingly mobilizes  T cells with immunosuppressive or tumour-promoting functions, thus emphasizing the importance of regulating  T cell responses to realize their translation into effective cancer immunotherapies. In this Review we outline both seminal work and recent advances in our understanding of how  T cells participate in tumour immunity and how their functions are regulated in experimental models of cancer. We also discuss the current strategies aimed at maximizing the therapeutic potential of human  T cells, on the eve of their exploration in cancer clinical trials that may position them as key players in cancer immunotherapy.

The hematopoietic landscape at single-cell resolution reveals unexpected stem cell features in naked mole-rats

“…Thymic TARP/JAML co-expression and an abundant CD4 -CD8cell fraction in blood raise the possibility that invariant TC receptor cells comprise the majority of the TC pool. While αβTCs primarily function in foreign antigen recognition, γδTCs mediate tissue homeostasis and damaged self recognition (Nielsen et al, 2017;Silva-Santos et al, 2019). The shift from αβTCtowards γδTC-mediated immunity may provide means to sustain tissue integrity and exert enhanced anti-tumor functions throughout their long lifespan.…”

Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

“…Remarkably, γδ T cell activation was the top enriched pathway among all immune-related processes, followed by natural killer (NK) cell-mediated immunitytwo of the key immune cell types involved in innate immune responses against cancer ( Fig. 1H) (21,22).…”

“…Our team developed a sequential cytokine stimulation protocol for selective expansion of Vδ1+ cells, the dominant γδ T cell subtype residing in the tissues, and a highly potent antitumor effector without the need for opsonizing antibodies in the tumor lytic process (24). γδ T cells are composed of heterogeneous subsets with pleiotropic immune effector functions (22). Our expansion protocol enriches γδ T cells with antitumor immunity instead of the protumor IL-17-producing γδ T subsets that have been shown to promote tumor progression (54,55).…”

Zoledronate rescues immunosuppressed monocytes in sepsis patients

“…A major physiological role of Vγ9/Vδ2 T‐cells is the sensing of microbial pathogens that produce the isoprenoid precursor ( E )‐4‐hydroxy‐3‐methyl‐but‐2‐enyl pyrophosphate (HMB‐PP), which include most Gram‐negative and many Gram‐positive bacteria . However, Vγ9/Vδ2 T‐cells also readily respond to stimulation with zoledronate, a clinically approved drug used successfully in patients with malignant and non‐malignant bone resorption disorders . This Vγ9/Vδ2 T‐cell response is dependent on monocyte uptake of zoledronate and involves the interruption of the intracellular mevalonate pathway, leading to accumulation of upstream intermediates such as isopentenyl pyrophosphate and recognition of sensitised monocytes via the butyrophilin‐like molecule BTN3 by the Vγ9/Vδ2 T‐cell receptor …”

“…17 However, Vc9/Vd2 T-cells also readily respond to stimulation with zoledronate, a clinically approved drug used successfully in patients with malignant and non-malignant bone resorption disorders. 17,18 This Vc9/Vd2 T-cell response is dependent on monocyte uptake of zoledronate 19 and involves the interruption of the intracellular mevalonate pathway, leading to accumulation of upstream intermediates such as isopentenyl pyrophosphate and recognition of sensitised monocytes via the butyrophilin-like molecule BTN3 by the Vc9/Vd2 T-cell receptor. 17,20,21 In co-culture experiments, cd T-cells activate monocytes, promote their survival, induce upregulation of markers associated with antigen-presenting cells (APCs) including HLA-DR, and enhance their APC function.…”