Entinostat induces antitumor immune responses through immune editing of tumor neoantigens
Andrew S. Truong, … , Benjamin G. Vincent, William Y. Kim
Andrew S. Truong, … , Benjamin G. Vincent, William Y. Kim
Published August 16, 2021
Citation Information: J Clin Invest. 2021;131(16):e138560. https://doi.org/10.1172/JCI138560.
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Research Article Oncology

Entinostat induces antitumor immune responses through immune editing of tumor neoantigens

Abstract

Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti–PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell–autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.

Authors

Andrew S. Truong, Mi Zhou, Bhavani Krishnan, Takanobu Utsumi, Ujjawal Manocha, Kyle G. Stewart, Wolfgang Beck, Tracy L. Rose, Matthew I. Milowsky, Xiaping He, Christof C. Smith, Lisa M. Bixby, Charles M. Perou, Sara E. Wobker, Sean T. Bailey, Benjamin G. Vincent, William Y. Kim

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Figure 6

Combination of entinostat and PD-1 inhibition confers effective and durable antitumor immunity.

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Combination of entinostat and PD-1 inhibition confers effective and dura...
(A) Box plots of PD-L1 (CD274) RNA expression of vehicle- and entinostat-treated BBN963 tumors from C57BL/6 mice. Significance was calculated using Mann-Whitney U test. (B) Average BBN963 tumor volume over time in response to entinostat and anti–PD-1 treatments. Significance was calculated using Wilcoxon’s matched-pairs signed rank test. n = 6–10 mice. (C) Waterfall plot of individual tumor volumes in B at end point relative to pretreatment baseline. (D) Survival curve of mice receiving entinostat and anti–PD-1 in B. Significance was calculated using log-rank test. End points were tumor burden and ulceration. (E) Bar graph indicating the percentages of control versus educated (entinostat plus anti–PD-1 treated) mice that developed detectable subcutaneous BBN963 tumors a month after rechallenge with BBN963 cells. Significance was calculated using Fisher’s exact test. Data are represented as mean ± SD. **P < 0.01.