Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells

Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection^1-3. This has been largely attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia², whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8⁺ T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45⁺ erythroid progenitor cells (CD71⁺TER119⁺; EPCs) as robust immunosuppressors. CD45⁺ EPCs, induced by tumor growth-associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (T_regs) and myeloid-derived suppressor cells (MDSCs). The CD45⁺ EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45⁺ EPC-mediated immunosuppression. Similarly, an immunosuppressive CD45⁺ EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.