PD-1 blockade alters fate commitment of myeloid progenitors during tumor-mediated “emergency” myelopoiesis

Abstract

Abstract PD-1 is an immune inhibitory receptor for which blocking agents have achieved significant success as anti-cancer therapeutics. The mechanism(s) of the how PD-1 compromises anti-tumor function and how such effect is reversed by PD-1 blockade remain poorly understood. The rapid change in hematopoietic output that occurs in response to immunologic stress is known as “emergency” myelopoiesis. This process is co-opted by tumors to enhance the generation of tumor-promoting myeloid cells, mostly undifferentiated myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We analyzed the myeloid compartment of tumor-bearing mice and determined that myeloid cells express PD-1 and PD-L1. Using PD-1 KO mice or WT mice treated with PD-1 blocking antibody in cancer-driven myelopoiesis experiments we determined a cell-switch fate from MDSCs to effector myeloid cells. PD-1 deletion or blockade, which impaired tumor growth and metastases, stimulated the differentiation of hematopoietic progenitor cells and resulted in increase of Ly6Chimonocytes and monocyte-derived DC (mo-DC). Abrogation of PD-1 signaling enhanced the maturation of MDSCs by inducing the lineage commitment transcription factors IRF8, IRF4 and RORC1. IRF8 and IRF4 promote monocytes/macrophage and hinder granulocyte differentiation, whereas RORC1 is required for expansion of Ly6Chi monocytes and resolution of inflammation. These results reveal a role of the PD-1:PD-L1 pathway in the differentiation of lineage-committed myeloid progenitors to promote undifferentiated MDSCs and suppress effector monocytes/DCs. Switch of myeloid progenitor fate commitment might be a key mechanism by which PD-1 blockade mediates anti-tumor function.