γδ T cells are significantly suppressed in glioma patients but retain their cytotoxic potential

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Abstract Complex interactions between tumor and immune cells influence γδ T cells in the course of glioma. The study aimed to characterise the γδ T cells in glioma patients and assess their potential for γδ T-based immunotherapy. Peripheral blood from 52 glioma patients and 30 healthy controls was collected. γδ T cells and their subsets were assessed by flow cytometry and compared between stages i.e. LGG and HGG. Cytokine expression and cytotoxicity against U251MG was tested on Vδ2 in vitro cultures. The co-culture of healthy donors PBMC with glioma patient plasma or 4 hours stimulations with U251MG were performed. Both total γδ T and Vδ1 cells were significantly expanded in glioma patients. While stimulatory molecules (CD226 and NKG2D) were downregulated, co-inhibitory molecules (PD-1, CTLA-4, TIGIT, TIM-3, LAG-3) were overexpressed. Suppression of γδ T cells seems to be promoted by circulating cytokines as PD-1, TIGIT, TIM-3, LAG-3 were upregulated in cultures with patient plasma. Healthy volunteer γδ T cells are usually significantly activated by U251MG as was demonstrated by an increase in CD69 and CD107a expression after short-term co-culture. Importantly, glioma patient-derived Vδ2 cells retained their cytotoxic potential against glioblastoma cells, even though they overexpressed anti-inflammatory cytokines (IL-10, TGF-β, IL-17). The results highlight the profoundly immunosuppressive peripheral blood environment in gliomas. Most importantly, this may significantly affect the general fitness of γδ T cells, lowering their potential for immunotherapy. On the other hand, those changes seem to be at least partially reversible as patient-derived γδ T cells retain their cytotoxic potential after in-vitro activation and culture. Supported by grant from Medical University of Lublin MG 25/2022.