Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy

Attenuated and heat-killed mycobacteria display demonstrable activity against cancer in the clinic; however, the induced immune response is poorly characterised and potential biomarkers of response ill-defined. We investigated whether three mycobacterial preparations currently used in the clinic (BCG and heat-killed Mycobacterium vaccae and Mycobacterium obuense) can stimulate anti-tumour effector responses in human gamma delta T-cells. gamma delta T-cell responses were characterised by measuring cytokine production, expression of granzyme B and cytotoxicity against tumour target cells. Results show that gamma delta T-cells are activated by these mycobacterial preparations, as indicated by upregulation of activation marker expression and proliferation. Activated gamma delta T-cells display enhanced effector responses, as shown by upregulated granzyme B expression, production of the T(H)1 cytokines IFN-gamma and TNF-alpha, and enhanced degranulation in response to susceptible and zoledronic acid-treated resistant tumour cells. Moreover, gamma delta T-cell activation is induced by IL-12, IL-1 beta and TNF-alpha from circulating type 1 myeloid dendritic cells (DCs), but not from type 2 myeloid DCs or plasmacytoid DCs. Taken together, we show that BCG, M. vaccae and M. obuense induce gamma delta T-cell anti-tumour effector responses indirectly via a specific subset of circulating DCs and suggest a mechanism for the potential immunotherapeutic effects of BCG, M. vaccae and M. obuense in cancer.