Robust T cell activation kills tumors regardless of T cell specificity

Immunotherapies putatively depend upon tumor-specific T cells. Here, we show how T cells can eliminate tumors without tumor-specificity via paracrine signaling. Activating unexhausted bystander non-tumor-specific T cells within tumors resulted in tumor elimination without conventional recognition-dependent mechanisms and in the absence of any tumor-specific TCRαâ T cell. Robust T cell activation recruited immune cells, utilized innate leukocytes, and triggered a tumoricidal combination of effector molecules and panoptotic pathways. Mechanistically, IFN-γ, TNF, and NO induced caspase-dependent death, recapitulating melanoma clearance in mice or human melanoma cell death in vitro. Gene expression signatures associated with this response in mice predicted survival among human melanoma patients. Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses.