Journal Article

Entinostat induces antitumor immune responses through immune editing of tumor neoantigens

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

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animal models / Animals / Antigen presentation / Antigens / Antigens, Neoplasm - drug effects / Antigens, Neoplasm - immunology / Antimitotic agents / Antineoplastic agents / Antineoplastic Agents, Immunological - pharmacology / Antitumor activity / Benzamides - pharmacology / Biomedical research / Bladder cancer / Cancer / Cancer therapies / Care and treatment / Cell cycle / Cell Line, Tumor / Editing / Enzyme inhibitors / Epigenetics / Flow cytometry / Gene expression / Genetic aspects / Health aspects / Histone Deacetylase Inhibitors - pharmacology / Humans / Hypotheses / Immune checkpoint inhibitors / Immune response / Immune system / Immunity - drug effects / Immunocompetence / Immunocompetence - drug effects / Immunotherapy - methods / Lymphocytes / Lymphocytes T / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / Mice, Knockout / Mice, SCID / Microenvironments / Mutation / Neoantigens / Oncology, Experimental / PD-1 protein / Pyridines - pharmacology / T-Lymphocytes - drug effects / Tumor antigens / Tumor Microenvironment - drug effects / Tumor Microenvironment - immunology / Tumors / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - immunology