Tumor-Induced Erythroid Precursor-Differentiated Myeloid Cells Mediate Immunosuppression and Curtail Anti-PD-1/PD-L1 Treatment Efficacy

Despite the unprecedented success of immune checkpoint inhibitors (ICIs) as anti-cancer therapy, it remains a prevailing clinical need to identify additional mechanisms underlying ICI therapeutic efficacy and potential drug resistance. Here, using lineage tracking in cancer patients and tumor-bearing mice, we demonstrate that erythroid progenitor cells lose their developmental potential and switch to the myeloid lineage. Single-cell transcriptome analyses reveal that, notwithstanding quantitative differences in erythroid gene expression, erythroid differentiated myeloid cells (EDMCs) are transcriptionally indistinguishable from their myeloid-originated counterparts. EDMCs possess multifaceted machinery to curtail T cell-mediated anti-tumor responses. Consequently, EDMC content within tumor tissues is negatively associated with T cell inflammation for the majority of solid cancers; moreover, EDMC enrichment, in accordance with anemia manifestation, is predictive of poor prognosis in various cohorts of patients undergoing ICI therapy. Together, our findings reveal a feed-forward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid transdifferentiation and immunosuppression. Overall design: To explore the differentiation of erythro-lineage cells, splenic CD11b-C-kit-CD45+Ter119+CD71+ cells (T-EPCs), and intratumoral CD45+Ter119+CD71+CD11b+Gr1+ (EDMCs) were isolated from LLC-bearing mice (day 21) and were subjected to scRNA-seq analysis. As references, splenic Ter119+CD71+ cells from acutely anemic mice (without specifying CD45 expression, A-EPCs), and overall intratumoral CD45+CD11b+Gr-1+ MDSCs (without specifying Ter119 or CD71 expression) were included in the analyses. For patient samples, CD235a+ bone marrow cells from bone-metastasis-free patients with advanced tumors, or CD45+CD235a+CD71+ cells from MPE were sorted, as indicated. ***Please note that raw data are not provided for the human samples*****