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 feedforward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid transdifferentiation and immunosuppression.
Long, H; Jia, Q; Wang, L; Fang, W; Wang, Z; Jiang, T; Zhou, F; Jin, Z; Huang, J; Zhou, L; Hu, C; Wang, X; Zhang, J; Ba, Y; Gong, Y; Zeng, X; Zeng, D; Su, X; Alexander, PB; Wang, L; Wang, L; Wan, YY; Wang, X-F; Zhang, L; Li, Q-J; Zhu, B
Volume / Issue
Start / End Page
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)