Hepatocellular carcinoma‐infiltrating γδ T cells are functionally defected and allogenic Vδ2⁺ γδ T cell can be a promising complement

Abstract

In hepatocellular carcinoma (HCC), γδ T cells participate in mediating the anti‐tumour response and are linked with a positive prognosis. However, these cells can become pro‐tumoural in the tumour microenvironment (TME). We aimed to decipher the immune landscape and functional states of HCC‐infiltrating γδ T cells to provide fundamental evidence for the adoptive transfer of allogeneic Vδ2 + γδ T cells in HCC immunotherapy. We performed single‐cell RNA sequencing (scRNA‐seq) on γδ T cells derived from HCC tumours and healthy donor livers. Confocal microscopy, flow cytometry and a Luminex assay were applied to validate the scRNA‐seq findings. The γδ T cells in the HCC TME entered G2/M cell cycle arrest, and expressed cytotoxic molecules such as interferon‐gamma and granzyme B, but were functionally exhausted as indicated by upregulated gene and protein LAG3 expression. The γδ T cells in the HCC TME were dominated by the LAG3 + Vδ1 + population, whereas the Vδ2 + γδ T population was greatly depleted. Moreover, glutamine metabolism of γδ T cells was markedly upregulated in the glutamine‐deficient TME. Both in vitro and in vivo experiments showed that glutamine deficiency upregulated LAG3 expression. Finally, our results indicated that ex vivo‐expanded Vδ2 + γδ T cells from healthy donor could complement the loss of T cell receptor clonality and effector functions of HCC‐derived γδ T cells. This work deciphered the dysfunctional signatures of HCC‐infiltrating γδ T cells in the HCC TME, providing scientific support for the use of allogeneic Vδ2 + γδ T cells in HCC cellular therapy.

Biological characteristics of γδT cells and application in tumor immunotherapy

“…Treg cells directly inhibit the effector function of γδT cells through cytokines TGFβ and IL-10 ( Yi et al, 2013 ). Studies have found that allogeneic Vδ2 + γδT cells can complement the loss of anti-tumor function of liver cancer-infiltrating γδT cells ( He et al, 2022 ). HCC tissue-resident γδT cells exhibit the characteristics of tissue-resident memory T cells and can effectively target ZOL-sensitized HCC tumor cells ( Zakeri et al, 2022 ).…”

In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

“…LAG-3 is another co-inhibitory receptor whose expression is transiently upregulated on effector cells following activation and more persistently expressed by Tregs, including thymic-derived Tregs, iTregs and Tr1 cells ( 272 ). While it is the most studied on T cells and Tregs, LAG-3 can also be expressed on unconventional T cells including gamma-delta T cells ( 273 ), mucosal-associated invariant T cells ( 274 ), invariant NKT cells ( 275 ), B cells ( 276 , 277 ), plasmacytoid DC ( 278 ) and neurons ( 279 ).…”

Revisit the signatures of γδ T cells in hepatocellular carcinoma

“…In this issue, He et al. 2 reveal the immune landscape, functional states, metabolism, cytotoxicity and T cell receptor (TCR) profiles of HCC‐infiltrating γδ T cells using single‐cell RNA sequencing (scRNA‐seq), which may facilitate the development of γδ T cell‐based immunotherapy.…”

“…Nevertheless, the immune signatures of γδ T cells are not fully understood at the single‐cell level, particularly in the context of the HCC tumour microenvironment (TME). In this issue, He et al 2 . reveal the immune landscape, functional states, metabolism, cytotoxicity and T cell receptor (TCR) profiles of HCC‐infiltrating γδ T cells using single‐cell RNA sequencing (scRNA‐seq), which may facilitate the development of γδ T cell‐based immunotherapy.…”