Robust T Cell Activation Kills Tumors Regardless of T Cell Specificity 2260126

Abstract

Solid tumors are populated with functional, non-circulating virus-specific CD8+ T cells, primed for rapid response to re-infection. Immunosurveillance by these memory T cells is evident across multiple tissues and solid tumors. Activation of these bystander cells triggers clearance of poorly immunogenic tumors in mice and is phenocopied in human tumor explants through unknown mechanisms — putatively involving the adjuvanting of tumor-specific T cell responses — providing the basis for a Phase I immunotherapy trial termed peptide alarm therapy (PAT). To define mechanisms of PAT mediated tumor clearance in murine models, we used single-cell multi-omics, targeted immune cell depletions, and genetic manipulations. We mapped how viral peptides influence antiviral T cell states and by what axes they signal to activate the innate and adaptive immune system to mount an effective response against malignant cells. We validated our multi-omic approach via in vivo studies to measure treatment efficacy in the context of key immune cell depletion and pathway inhibitions. We initially hypothesized that tumors were cleared in an antigen-specific manner; however, PAT cured without conventional recognition-dependent mechanisms and in the absence of any tumor-specific TCRab T cell. Mechanistically, robust T cell activation recruited immune cells, utilized innate leukocytes, and triggered a tumoricidal combination of effector molecules and panoptotic pathways, resulting in tumor-specific clearance independent of conventional T cell mechanisms. IFN-γ, TNF, and NO induced caspase-dependent death, recapitulating melanoma cures in mice or human melanoma cell death in vitro. Gene expression signatures of immune and tumor cell types involved in this panoptotic pathway were predictive of 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. F30CA253992, R01CA238439, DP1238659 Computational and Systems Immunology (COMP)