Abstract 3279: All-trans-retinoic acid (ATRA) markedly augments anti-tumor immunity

Abstract

Abstract All-trans-retinoic acid (ATRA) engages diverse actions on populations of immune cells. These include effects on regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), Th17 and other immune cells. Prior work found that ATRA can induce anti-tumor immunity through MDSCs and CD8+ T cells and pro-tumor immunity by increasing Treg cells. In this study, we explored how ATRA modulated anti-tumor immunity in solid tumors. To do this, syngeneic lung cancer and colon cancer models were independently developed by optimizing subcutaneous injections of ED1SQ4 lung cancer and MC38 colon cancer cells into immune-competent mice. ATRA-treatment markedly repressed both syngeneic lung cancer and colon cancer growth as compared to vehicle-treated mice. To exclude the possibility that ATRA directly suppressed growth of cancer cells, ED1SQ4 and MC38 cells were independently implanted subcutaneously into athymic mice in order to allow these lung and colon cancer xenografts to grow. Notably, ATRA-treatment did not reduce the growth of these respective xenograft tumors. Intriguingly, ATRA did not suppress in vitro proliferation of either ED1SQ4 or MC38 cells. This implicated ATRA as engaging mechanisms that affect the tumor microenvironment. To learn if the observed anti-tumorigenic activity was mediated by regulation of T cell immunity, CD4+ or CD8+ T cell populations were depleted in syngeneic mice before in vivo ATRA-treatment. CD4+ and CD8+ T cell depletion from syngeneic mice at least partially reversed the tumor suppressive activity of ATRA. Flow cytometry assays conducted on intratumoral immune cells revealed that ATRA-treatment decreased the CD8+ T to Treg cellular ratios while increasing the ratios of CD8+ T to Treg cells. Cytokine and chemokine assays were performed on these syngeneic cancers as well as on peripheral blood harvested from ATRA or vehicle-treated syngeneic mice in order to identify mediators of the observed anti-tumorigenic effects. Findings will be presented. Taken together, this study uncovered a previously unrecognized role for ATRA in augmenting immunotherapy. These preclinical immunotherapy findings can be translated into the cancer clinic. Citation Format: Lu Huang, Zibo Chen, Leila Williams, Yulong Chen, Yunfei Wang, Masanori Kawakami, Jason Roszik, Patrick Hwu, Ethan Dmitrovsky, Weiyi Peng, Xi Liu. All-trans-retinoic acid (ATRA) markedly augments anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3279.