Vγ9Vδ2 T Cell Response to Colon Carcinoma Cells

Abstract

During analysis of CD8 T cells derived from ascites of a colon cancer patient, we isolated a Vγ9Vδ2 T cell clone showing strong reactivity against autologous tumor cell lines. This clone killed a large fraction of allogeneic colon carcinoma and melanoma cell lines, but did not affect a normal colon cell line, colon fibroblasts, or melanocytes. Tumor cell recognition was TCR and NKG2D dependent and induced TNF-α and IFN-γ secretion by the clone; accordingly, tumor targets expressed several NKG2D ligands, such as MHC class I chain-related gene A and UL16-binding protein molecules. Colon tumor recognition by Vγ9Vδ2 T cells was highly dependent on isopentenyl pyrophosphate production and ICAM-1 expression by target cells. Finally, similar reactivity patterns against colon carcinoma cell lines were observed using polyclonal Vγ9Vδ2 T cells of various origins, and Vγ9Vδ2 lymphocytes were present in the majority of colon tumor samples studied. Together, these results suggest that Vγ9Vδ2 T cells contribute to the natural immune surveillance against colon cancers. Therefore, this study provides a strong rationale for the use of Vγ9Vδ2 T cell agonists in immunotherapies targeting colon tumors.

DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

“…The capacity of gd T cells to recognize human tumor cells in a nonrestricted MHC manner is well documented [3,4,7,9]. However, the requirements for recognition of malignant cells are not completely understood.…”

“…Immunological approaches using innate antitumor effector cells are currently being evaluated in clinical trials [2]. Vg9Vd2 T cells represent the major population of human peripheral blood gd T cells and display an in vitro non-MHCrestricted lytic activity against a broad panel of tumors including colon, kidney, liver, esophageal, small-lung cancers and myeloma [3][4][5][6][7][8][9]. The presence of tumor-infiltrating Vd2 1 T cells in tumorbearing livers of patients may support their potential role in tumor immunosurveillance of HCC [10].…”

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Accordingly, tumor-infiltrating gamma delta T lymphocytes (cd TILs) were detected in a broad spectrum of malignancies. [5][6][7] cd TILs, primarily of the Vc9Vd2 cd T cell type, were reported in renal cell carcinomas, albeit with controversial prognostic values. [7][8][9][10] Nasopharyngeal carcinoma patients carry Vc9Vd2 cd T lymphocytes that are functionally impaired in blood 11 but are able to infiltrate and reduce xenografted nasopharyngeal tumors in mice.…”

“…16 In breast, ovarian, prostate and colorectal cancers, cd TILs also included cells that were negative for the Vc9Vd2 TCR. [5][6][7] Vd1 1 cd TILs are present in melanoma, and the infiltration of these cells into necrotizing melanoma correlates with survival. 17 Orthotopic xenografts of the HT29 colon cancer cells in mice infused with human TCRVd2 2 cd T lymphocytes also carried cd TILs that impaired tumor development.…”

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity

“…cdT cells can directly recognize antigens without MHC restriction, 12 have a wide antigen recognition spectrum, which includes protein antigens and phosphoantigens 13 and can directly kill several tumor types including colorectal, lung, prostate, ovarian and renal cell carcinomas. 16,18,25,28,29 Because of these features, cdT cells are an interesting candidate effector for antitumor immune therapy. There are two commonly available strategies for using cdT cells in cancer therapy.…”