Chiu et al. uncovered the role of tumoral erythropoietin (EPO) in immune-cold tumor microenvironments in hepatocellular carcinoma models. EPO overexpression resulted in increased levels of Tregs and immunoregulatory macrophages, in particular, EPO receptor (EPOR)-expressing Tim4+ Kupffer cells. Inhibition of EPO/EPOR signaling increased CD8+ T cell infiltration, induced tumor regression, and worked synergistically with PD-1 blockade. The effects were NRF2-mediated, resulting in a reduction in heme levels in macrophages.
ABSTRACT: 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 a noninflamed 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 noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. (2) Department of Pathology, Stanford University, Stanford, CA, USA. (3) Stanford Institute for Immunity, Trans
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. (2) Department of Pathology, Stanford University, Stanford, CA, USA. (3) Stanford Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. (4) Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA. (6) ImmunEdge Inc., Mountain View, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA. (8) Department of Pathology, Stanford University, Stanford, CA, USA. (9) Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA. (10) Advanced Drug Delivery and Regenerative Biomaterials Laboratory, Cardiovascular Institute, Department of Medicine, Stanford University, Stanford, CA, USA. (11) Department of Otolaryngology-Head and Neck Surgery, Stanford University, Stanford, CA, USA. (12) Department of Radiation Oncology, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA. Stanford Cancer Institute, Stanford University, Palo Alto, CA, USA.
