Bacterial outer-membrane vesicles promote Vγ9Vδ2 T cell oncolytic activity

Background: Increasing evidence suggests the immune activation elicited by bacterial outer-membrane vesicles (OMVs) can initiate a potent anti-tumor immunity, facilitating the recognition and destruction of malignant cells. At present the pathways underlying this response remain poorly understood, though a role for innate-like cells such as gamma delta T cells has been suggested. Methods: Peripheral blood mononuclear cells (PBMCs) from healthy donors were co-cultured with E. coli MG1655 Delta pal Delta lpxM OMVs and corresponding immune activation studied by cell marker expression and cytokine production. OMV-activated gamma delta T cells were co-cultured with cancer cell lines to determine cytotoxicity. Results: The vesicles induced a broad inflammatory response with gamma delta T cells observed as the predominant cell type to proliferate post-OMV challenge. Notably, the majority of gamma delta T cells were of the V gamma 9V delta 2 type, known to respond to both bacterial metabolites and stress markers present on tumor cells. We observed robust cytolytic activity of V gamma 9V delta 2 T cells against both breast and leukaemia cell lines (SkBr3 and Nalm6 respectively) after OMV-mediated expansion. Conclusions: Our findings identify for the first time, that OMV-challenge stimulates the expansion of V gamma 9V delta 2 T cells which subsequently present antitumor capabilities. We propose that OMV-mediated immune activation leverages the anti-microbial/anti-tumor capacity of V gamma 9V delta 2 T cells, an axis amenable for improved future therapeutics.