Intratumoral T cell activation kills tumors regardless of T cell specificity

Immunotherapies putatively require 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 T cell receptor (TCR)αβ⁺ T cells. Robust T cell activation recruited immune cells, used innate leukocytes and triggered a tumoricidal combination of effector molecules and panoptotic pathways. Mechanistically, interferon-γ, tumor necrosis factor and nitric oxide 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 were predictive of survival among human patients with melanoma. Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses.