Function of γδ T cells in tumor immunology and their application to cancer therapy

Abstract

T cells of the γδ lineage are unconventional T cells with functions not restricted to MHC-mediated antigen presentation. Because of their broad antigen specificity and NK-like cytotoxicity, γδ T-cell importance in tumor immunology has been emphasized. However, some γδ T-cell subsets, especially those expressing IL-17, are immunosuppressive or tumor-promoting cells. Their cytokine profile and cytotoxicity are seemingly determined by cross-talk with microenvironment components, not by the γδTCR chain. Furthermore, much about the TCR antigen of γδ T cells remains unknown compared with the extreme diversity of their TCR chain pairs. Thus, the investigation and application of γδ T cells have been relatively difficult. Nevertheless, γδ T cells remain attractive targets for antitumor therapy because of their independence from MHC molecules. Because tumor cells have the ability to evade the immune system through MHC shedding, heterogeneous antigens, and low antigen spreading, MHC-independent γδ T cells represent good alternative targets for immunotherapy. Therefore, many approaches to using γδ T cells for antitumor therapy have been attempted, including induction of endogenous γδ T cell activation, adoptive transfer of expanded cells ex vivo, and utilization of chimeric antigen receptor (CAR)-T cells. Here, we discuss the function of γδ T cells in tumor immunology and their application to cancer therapy.

Fig. 1. Network of antitumor γδ T cells.

γδTCR ligands such as phosphoantigens can bind to γδTCR. Stress-induced molecules, including MICA/B and Rae-1, can bind to NK receptors such as NKG2D. This ligation induces activation of antitumor γδ T cells. Proinflammatory cytokines, such as IFNγ and TNF, can further activate antitumor immunity by inducing MHC molecules on the tumor cell surface or by affecting other immune cells. The upregulation of cytotoxic molecules such as granzymes and perforin can directly kill tumor cells. In addition to these receptors, FcR-mediated ADCC, FAS-FASL, and TRAIL ligation can also induce direct cytotoxicity against tumor cells. γδ T cells can promote B cells to produce IgE, which has an antitumor effect.

Fig. 2. The role of protumor γδ T cells.

Tumor-promoting γδ T cells express RORγt and STAT3 to promote IL-17 production, as well as Foxp3, which is a marker of regulatory T cells. IL-17 secreted from γδ T cells promotes tumor cell proliferation and migration, which can provoke metastasis to distant organs. γδ T cell-derived IL-17 induces MDSC differentiation from granulocytes such as neutrophils and the M2 phenotype acquisition of macrophages. γδ T cells promote metastasis through angiogenesis and suppress immune cells. IL-4 produced from tumor-promoting γδ T cells skews CD4 T cells to differentiate into Th2 cells and inhibits Th1 responses. IL-10 secreted from γδ T cells further inhibits T cells. In addition, surface expression of PD-L1 attenuates PD-1-expressing lymphocytes.

Fig. 3. Regulation of γδ T cells.

a Although there are exceptions, γδ T cells generally do not express CD4 or CD8. Therefore, SFK-mediated activation cannot be used to activate γδ T cells. However, the ERK pathway is activated. For the normal development of γδ T cells, TCR signaling is important. T10/T22 and Skint1 are well-defined antigens for γδTCR. T10/T22-mediated signaling induces IFNγ-producing γδ T cells, whereas the Skint1 signaling induces DETC development. Some innate subsets of γδ T cells do not require TCR stimulation during development. Although several reports have demonstrated that innate IL-17-producing γδ T cells do not require TCR signaling, other studies have shown that TCR specificity or Zap70 phosphorylation is needed for full γδ T cell activation. b Coinhibitory molecules, including PD-1, CTLA4, and BTLA, can suppress γδ T cells. PD-1 and BTLA are frequently expressed by γδ T cells. However, CTLA4 is rarely expressed on the γδ T cell surface. Costimulatory molecules such as CD28, CD27, and 4-1BB are needed for development or activation. CD28 is needed for advancing disease conditions but not its development. However, CD27 is needed for the development and proper expression of IFN-γ. 4-1BB is known to enhance Vγ9Vδ2 T cells. However, the roles and mechanisms of these and other coinhibitory/stimulatory molecules remain unclear. c Various cytokines induce γδ T cell differentiation, leading to different functions. The γδ T-cell differentiation dichotomy is mainly affected by cytokine signals.

Fig. 4. Clinical implication of using γδ T cells.

Antitumor therapies using γδ T cells are currently being developed. PBMCs from patients can be expanded under TCR- and cytokine-stimulating conditions. Expanded γδ T cells can kill tumor cells in vitro. Patient-derived cells can be transduced with engineered γδTCR. γδ CAR-T cells have the potential to be used for therapy. γδTCR-transduced αβ T cells (TEGs) are thought to be effective therapeutic agents. Injection of antibodies against costimulatory molecules or anti-inhibitory molecules can be used to reinvigorate γδ T cells. Reagents, such as zoledronate, can be used to activate γδ T cells de novo.