B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells

Abstract

The immunoregulatory protein B7-H3, a member of the B7 family, has been confirmed to be highly expressed in colon cancer. However, the exact influence of B7-H3 on the features and antitumor ability of γδT cells in colon cancer remains unknown. In the present study, we investigated that the proportions of B7-H3 + γδT cells were distinctly increased in the peripheral blood and tumor tissues of colon cancer patients. B7-H3 blockade or knockdown promoted proliferation, inhibited cell apoptosis and induced the expression of activation markers (CD25 and CD69) on Vδ2 T cells. In contrast, treatment with the B7-H3 agonist 4H7 had the opposite effect. Furthermore, B7-H3 suppressed IFN-γ expression by inhibiting T-bet in Vδ2 T cells. Moreover, B7-H3 mediated the inhibition of Vδ2 T cell cytotoxicity via the downregulation of IFN-γ and perforin/granzyme B expression. More importantly, blocking the B7-H3 function significantly enhanced the cytotoxicity of Vδ2 T cells against colon cancer cells in vivo. Therefore, the inhibition or blockade of B7-H3 is a potential immunotherapeutic approach for colon cancer.

H19 contributes to aerobic glycolysis, proliferation and immune escape of gastric cancer cells via the miR-519d-3p/LDHA axis

“…Based on our data that H19 affected the lactate accumulation, we concluded that H19 might modulate tumor immune response in a lactate dependent manner. Our and others' studies showed that γδT cells have important roles in tumor immunosurveillance against multiple malignancies such as colorectal cancer and leukemia [29,49]. Importantly, tumor-in ltrating γδT cells were an independent prognostic factor in GC patients and could predict the survival bene t of adjuvant chemotherapy in patients with TNM II and III diseases [50].…”

“…γδT cell separation and culture γδT cells were isolated from human peripheral blood mononuclear cells (PBMCs) and cultured as our previously described [29].…”

Gut γδ T cells as guardians, disruptors, and instigators of cancer

“…These observations indicate that the tumor microenvironment may influence the ability of γδ T cells to recognize cancer cells. In support of this notion, the characterization of Vγ9Vδ2 cells in CRC patients with liver metastasis treated with standard of care, 5‐fluorouracil/oxaliplatin (FOLFOX), has shown that absolute numbers of circulating Vγ9Vδ2 cells are reduced 223,224 . Vγ9Vδ2 cells in these patients exhibit a higher frequency of terminally differentiated and senescent phenotype with impaired effector function, when compared to Vγ9Vδ2 cells from healthy donors.…”

“…manner. 291 Blocking B7-H3 on Vγ9Vδ2 cells increases colorectal cancer cell line killing in vitro and in vivo, 224 suggesting that interfering with B7-H3 signaling may further improve cytotoxicity by these cells. Thus, Vγ9Vδ2 cells may provide a safe and effective form of immunotherapy for CRC patients.…”

“…Similarly, Vγ9Vδ2 cells from the peripheral blood of CRC patients that are expanded ex vivo with BrHPP and IL‐2 acquire an effector phenotype and show strong lytic activity specifically toward tumor cells in both a TCR‐ and NKG2D‐mediated manner 291 . Blocking B7‐H3 on Vγ9Vδ2 cells increases colorectal cancer cell line killing in vitro and in vivo, 224 suggesting that interfering with B7‐H3 signaling may further improve cytotoxicity by these cells. Thus, Vγ9Vδ2 cells may provide a safe and effective form of immunotherapy for CRC patients.…”