Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors
Significance Immunosuppressive tumor microenvironment, insufficient migration, and reduced effector function of tumor-specific T cells are the main hurdles that hamper the efficacy of immunotherapy in treating solid tumors. In this study, we combined the strength of adoptive cell transfer (ACT) and pathogen-based cancer vaccine and developed an innovative strategy, Reenergized ACT (ReACT), to treat solid tumors. ReACT uses a pathogen not only to break the immunosuppression, but also to drive the expansion and migration of tumor-specific T cells to the site of the tumor. With this combinatorial approach, we have demonstrated that ReACT enhances antitumor efficacy in comparison with either ACT or pathogen-based cancer vaccine alone in primary tumor eradication and offers long-term protection against reoccurrence in preclinical cancer models. Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.
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