Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy.

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.

• Authors: Haixia Long, Qingzhu Jia, Liuyang Wang, Wenfeng Fang, Zhongyu Wang, Tao Jiang, Fei Zhou, Zheng Jin, Jiani Huang, Li Zhou, Chunyan Hu, Xinxin Wang, Jin Zhang, Yujie Ba, Yujie Gong, Xianghua Zeng, Dong Zeng, Xingxing Su, Peter B Alexander, Li Wang, Limei Wang, Yisong Y Wan, Xiao-Fan Wang, Li Zhang, Qi-Jing Li, Bo Zhu
• Journal: Cancer cell (Cancer Cell) Vol. 40 Issue 6 Pg. 674-693.e7 (06 13 2022) ISSN: 1878-3686 [Electronic] United States
• PMID: 35594863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen

Topics

• Anemia (genetics, metabolism)
• Animals
• B7-H1 Antigen (metabolism)
• Erythroid Precursor Cells
• Humans
• Immunosuppression Therapy
• Mice
• Myeloid Cells (metabolism)
• Neoplasms (therapy)
• Treatment Outcome
• Tumor Microenvironment