Using lineage tracking, Long, Jia, and Wang et al. demonstrated that erythroid progenitor cells can lose their developmental potential and switch to a myeloid lineage (erythroid differentiated myeloid cells: EDMCs) with robust immunosuppressive potential. Tumor cell-produced GM-CSF mediated the differentiation of erythroid precursors toward EDMCs, which expressed higher levels of immunosuppressive molecules, accelerated tumor growth, and attenuated anti-PD-L1 therapy efficacy in tumor models. Elevated EDMC scores correlated with CD8+ T cell exhaustion, and patients with moderate-to-severe anemia showed significantly reduced responses to ICI treatment.
Contributed by Shishir Pant
ABSTRACT: 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.