Loss of target antigens in tumor cells has become one of the major hurdles limiting the efficacy of adoptive cell therapy (ACT)–based immunotherapies. The optimal approach to overcome this challenge includes broadening the immune response from the initially targeted tumor-associated antigen (TAA) to other TAAs expressed in the tumor. To induce a more broadly targeted antitumor response, we utilized our previously developed Re-energized ACT (ReACT), which capitalizes on the synergistic effect of pathogen-based immunotherapy and ACT. In this study, we showed that ReACT induced a sufficient endogenous CD8 + T-cell response beyond the initial target to prevent the outgrowth of antigen loss variants in a B16-F10 melanoma model. Sequentially, selective depletion experiments revealed that Batf3-driven cDC1s were essential for the activation of endogenous tumor-specific CD8 + T cells. In ReACT-treated mice that eradicated tumors, we observed that endogenous CD8 + T cells differentiated into memory cells and facilitated the rejection of local and distal tumor rechallenge. By targeting one TAA with ReACT, we provided broader TAA coverage to counter antigen escape and generate a durable memory response against local relapse and metastasis. See related Spotlight on p. 2 Footnotes Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/). Cancer Immunol Res 2020;8:7–18 Received April 4, 2019. Revision received September 6, 2019. Accepted November 1, 2019. Published first November 12, 2019. ©2019 American Association for Cancer Research. Log in using your username and password Username * Forgot your user name or password? Purchase access You may purchase access to this article. This will require you to create an account if you don't.
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