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 neutropenia 2 , 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 reg s) 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. Large tumors induce anemia and expansion of CD45 + immature erythroid cells, which represent a major immunosuppressive population in the spleen, contributing to systemic suppression of T cell immunity in late-stage cancer.