While the effector cells that mediate anti-tumor immunity have historically been attributed to αβ T cells and natural killer cells, γδ T cells are now being recognized as a complementary mechanism mediating tumor rejection. γδ T cells possess a host of functions ranging from antigen presentation to regulatory function and, importantly, have critical roles in eliciting anti-tumor responses where other immune effectors may be rendered ineffective. Recent discoveries have elucidated how these differing functions are mediated by γδ T cells with specific T cell receptors and spatial distribution. Their relative resistance to mechanisms of dysfunction like T cell exhaustion has spurred the development of therapeutic approaches exploiting γδ T cells, and an improved understanding of these cells should enable more effective immunotherapies.

Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.

Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2^- γδ T cells, with equivalent representation of Vδ1⁺ and Vδ1^- cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2^- T cells can express the transcriptional program of exhausted αβ CD8⁺ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2^- γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2^- γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2^- T-cell receptors. Human tumor-derived Vδ2^- γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2^- T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2^- γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.