Impaired immunity in late stage cancer patients is not limited to anti-tumor 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-naïve 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 (Tregs) 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 cancer patients with anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in advanced cancer patients.

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