Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-γ signaling

Proceedings of the National Academy of Sciences of the United States of America
Anthony C AntonelliGil Redelman-Sidi

Abstract

Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer is the only bacterial cancer therapy approved for clinical use. Although presumed to induce T cell-mediated immunity, whether tumor elimination depends on bacteria-specific or tumor-specific immunity is unknown. Herein we show that BCG-induced bladder tumor elimination requires CD4 and CD8 T cells, although augmentation or inhibition of bacterial antigen-specific T cell responses does not alter the efficacy of BCG-induced tumor elimination. In contrast, BCG stimulates long-term tumor-specific immunity that primarily depends on CD4 T cells. We demonstrate that BCG therapy results in enhanced effector function of tumor-specific CD4 T cells, mainly through enhanced production of IFN-γ. Accordingly, BCG-induced tumor elimination and tumor-specific immune memory require tumor cell expression of the IFN-γ receptor, but not MHC class II. Our findings establish that a bacterial immunotherapy for cancer is capable of inducing tumor immunity, an antitumor effect that results from enhanced function of tumor-specific CD4 T cells, and ultimately requires tumor-intrinsic IFN-γ signaling, via a mechanism that is distinct from other tumor immunotherapies.

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Citations

Jan 30, 2021·Targeted Oncology·Michael A MorseDuane A Mitchell
Aug 31, 2020·European Urology·Roger LiAshish M Kamat
Jun 3, 2021·Vaccines·Fabíola CardilloRosa Teixeira Pinho
Jul 13, 2021·Frontiers in Oncology·Yang DongCong-Hui Han
Jul 17, 2021·Journal for Immunotherapy of Cancer·Erkko YlösmäkiVincenzo Cerullo

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