Abstract B164: Inhibiting glycolysis enhances imiquimod-induced immunogenic cell death and the antitumor immune response

Immunogenic cell death (ICD) characterized as cells undergo with ICD could elicit a specific immune response to against a subsequent challenge with the same type living cells. Imiquimod (IMQ), a synthetic Toll-like receptor 7 ligand, is a imidazoquinoline family member and contains both antitumor and antiviral activity. IMQ is currently clinical used in topical, noninvasive treatment for various skin malignances. IMQ exerts its anti-tumoral activity through stimulating TLR7/8 in dendritic cells and activate cell-mediated immune responses, and directly induces tumor cell death. Recently, we had demonstrated IMQ directly induced autophagic cell death and apoptosis to against tumor cells that independent of TLR7/8. Thus, IMQ may induce tumor undergo ICD to trigger specific antitumor immune response. We found that IMQ induced expression of ICD-associated features in various cancer cell lines. We demonstrated that vaccination of IMQ-induced ICD cell lysate provided significant antitumor immunity with increased CD4 and CD8 T lymphocytes proliferation, tumor-specific cytotoxic lysis and infiltration of CD4, CD8, CD11c and IL-17A-producing cells in tumor lesion. Pharmacologic inhibition and genetic manipulation of ICD-associated features repressed IMQ-treated cell lysate-mediated specific anti-tumor immunity. We also found that IMQ-induced ICD-associated features is mediated by ROS production and ER stress through PERK/eIF2α pathway. In addition, inhibition of glycolysis significantly enhanced IMQ-induced ICD cell lysate-mediated antitumor immunity and ICD-associated features. Taken together, these results provided solid evidence to support that IMQ is an authentic ICD inducer and independent of TLR7/8 expression, and targeting aerobic glycolysis could be a desirable strategy to enhance IMQ-induced ICD and antitumor immunity. Citation Format: Shi-Wei Hunag, Jeng-Jer Shieh, Sin-Ting Wang, Der-Yang Cho, Shao-Chih Chiu. Inhibiting glycolysis enhances imiquimod-induced immunogenic cell death and the antitumor immune response [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B164.