Abstract 2941: Inhibition of hypoxia-induced ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2) restrains myeloid-derived suppressor cell (MDSC) accumulation and sensitizes tumors to immune checkpoint inhibition

Abstract

Abstract Background and Objective: Rapidly expanding knowledge on cancer immunology has introduced promising anti-cancer therapeutic approaches which involve the activation of T cells to combat cancer cells. Accumulating studies have indicated that the efficacy of immunotherapies is critically determined by the stromal cell components in tumors. Myeloid-derived suppressor cells (MDSCs), are regarded as one of the major immune cell types that possess immunosuppressive activities against T cells which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. To increase the efficacy of immunotherapy, novel strategies to target MDSC in tumors are warranted. Hypoxia, oxygen (O2) shortage, frequently occurs in tumors due to abnormal vasculature. Using hepatocellular carcinoma (HCC) as a model, we have previously observed MDSC preferentially accumulates in hypoxic regions of human HCC tissues. Here, we aim to identify hypoxia-induced therapeutic targets that are critical for MDSC accumulation in tumors. Experimental Procedures: Transcriptome sequencing in multiple HCC cell lines exposed to hypoxia and normoxia and HCC clinical specimens was performed to identify potential hypoxia-induced genes relevant to HCC development. MDSCs were isolated from HCC-bearing mice by magnetic bead sorting for different functional assays. LC-MS was performed to evaluate the level of extracellular metabolites. Flow cytometry was used to detect the frequencies of tumor-infiltrating MDSCs in orthotopic and subcutaneous HCC mouse models. Results: We showed that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induced ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/ CD39L1), in cancer cells, causing its over-expression in HCC clinical specimens. Over-expression of ENTPD2 was found as a poor prognostic indicator for HCC patients. Mechanistically, we demonstrated that ENTPD2 converted extracellular ATP to 5’-AMP which prevents the differentiation of monocytic MDSCs to dendritic cells, therefore promoting the maintenance of MDSCs in vitro and in vivo. Therapeutically, we found that ENTPD2 inhibitor POM-1 restrained MDSC accumulation and tumor growth, substantially enhancing the efficiency and efficacy of immune checkpoints inhibitors. Conclusion: Our study reveals a novel mechanism whereby hypoxia/HIF-1 in cancer cells governs tumor-infiltrating MDSCs. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients especially those receiving immune therapy. Citation Format: David Kung-Chun Chiu, Aki Pui-Wah Tse, Iris Ming-Jing Xu, Robin Kit-Ho Lai, Hui-yu Koh, Felice Ho-Ching Tsang, Larry Lai Wei, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. Inhibition of hypoxia-induced ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2) restrains myeloid-derived suppressor cell (MDSC) accumulation and sensitizes tumors to immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2941. doi:10.1158/1538-7445.AM2017-2941