Tumor-accumulating Salmonella Reinvigorates Tissue-resident Memory (TRM)-like CD8T Cells Against Solid Tumors Through Interleukin-10 

腫瘤靶向沙門氏菌通過刺激白細胞介素-10分泌激活組織駐留記憶(TRM)樣CD8+ T細胞殺傷實體瘤

Student thesis: Doctoral Thesis

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Award date4 Sept 2023


The failure to elicit potent immune response in the solid tumor microenvironment (TME) present a major limitation to the application of state-of-the-art immunotherapy, such as immune checkpoint inhibitors and adoptive cell transfer. The condensed tissue structure and irregular blood vessel of solid tumors resist the infiltration of therapeutic agents. And the immunosuppressive TME further renders these agents in a dysfunctional state. We have programmed a Salmonella enterica strain DB1 to exclusively thrive in solid tumors but were quickly depleted in normal organs as administrated intravenously. On solid tumor models these bacteria robustly showed therapeutic efficacy and elicited long-term immune memory against tumor recurrence and metastasis. The therapeutic effects primarily stem from the local reinvigoration and expansion of the pre-existing exhausted tumor tissue-resident memory (TRM)-like CD8+ T cells in TME. Our analysis revealed that the revitalization of exhausted TRM-like CD8+ T cells was mediated by interleukin-10 (IL-10)/IL-10 receptor (IL-10R) signaling. The IL-10 was predominantly produced by tumor-associated macrophages (TAM) in response to the bacterial colonization of solid tumors. Further, we found that the intratumoral preexistence of IL-10R not only primed TRM-like CD8+ T cells for reinvigoration, but also promoted TAM for producing IL-10 and facilitated bacterial evasion from tumor-associated neutrophil phagocytosis. These results reveal the unsolved mechanism underlying bacterial cancer therapy, suggesting IL-10R expression as a new predictor for immunotherapy responses, and pave a way toward new therapeutic approaches for solid tumor non-invasive treatments by bacterially intratumoral immunomodulation.