Renal Cell Carcinoma-Infiltrating CD3low Vγ9Vδ1 T Cells Represent Potentially Novel Anti-Tumor Immune Players

Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (gamma delta) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human gamma delta T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify gamma delta T cells that might have adaptive responses against RCC progression. We characterized gamma delta T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between gamma delta T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3(low) V gamma 9V delta 1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, gamma delta T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, exhausted T cells, and M1 macrophages, suggesting active involvement of gamma delta T cells in anti-tumor rather than pro-tumor activity, and V delta 1 cells were more abundant than V delta 2 or V delta 3 cells in RCC tumor samples. Thus, we posit that V gamma 9V delta 1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery.

Automated summary

Research indicates that gamma delta T cells play a crucial role in RCC, especially with V delta 1 cells being the predominant tumor-infiltrating lymphocytes with high cytotoxic activity and correlation with anti-cancer immune activity.