The role of hypoxia on myeloid-derived suppressor cell accumulation in hepatocellular carcinoma

Abstract

Rapidly expanding knowledge in cancer immunology has introduced new promising therapeutic approaches involving 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 contribute to tumor immunosuppression and escape of immune surveillance. In order to increase the efficacy of immunotherapy, novel strategies against MDSCs in tumors are warranted. Hypoxia, O2 deprivation, is an important factor in the microenvironment of solid cancers whose growth often exceeds growth of blood vessels. Using hepatocellular carcinoma (HCC) as the cancer model, we observed that MDSCs preferentially accumulate in hypoxic regions in human HCC tissues. We identified two novel hypoxia-induced genes, (C-C motif) ligand 26 (CCL26) and ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), via analysis of transcriptomes of clinical specimens and HCC cell lines and further assessment of their roles in MDSC accumulation. Hypoxia-induced MDSC accumulation is dependent on hypoxia-inducible factors (HIFs). HIFs activate the transcriptions of CCL26 and ENTPD2 in cancer cells. CCL26 recruits chemokine (C-X3-C motif) receptor 1 (CX3CR1)-expressing MDSCs to the primary tumor while ENTPD2 converts extracellular ATP into 5’-AMP, which prevents MDSC differentiation to dendritic cells. Therapeutically, we demonstrate that inhibition of CX3CR1 or ENTPD2 can substantially reduce tumor-infiltrating MDSC population and increase the efficacy of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/ programmed cell death protein 1 (PD-1) blockade immunotherapy. Our study unprecedentedly reveals the novel molecular mechanisms by which cancer cells promote MDSCs accumulation in tumor sites and suggests that targeting MDSC accumulation as a new therapeutic strategy against solid cancers.