Bulk RNA-seq of Kupffer cells from Hepa1-6_EV (empty vector) and Hepa1-6_EpoOE (overexpression) HCC-bearing C57BL/6 mice
Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors, however many cancers evade the body's immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T-cell-rich or non-inflamed T-cell-deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a non-inflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory via NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, due to augmented antitumor T-cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for anti-tumor immunity. Overall design: Kupffer cells (KCs) were isolated by FACS from liver tissues of Hepa1-6_EV (KC_EV) and Hepa1-6_EpoOE (KC_Epo) HCC-bearing mice at day 18 post-implantation. KC_EV and KC_Epo were analyzed with flow cytometry and subjected to bulk RNA-seq.