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.
Author Info: (1) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (2) Institute of Cancer
Author Info: (1) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (2) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (3) Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA. (4) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. (5) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (6) Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China. (7) Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China. (8) Research Institute, GloriousMed Clinical Laboratory (Shanghai) Co., Ltd, Shanghai, China. (9) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (10) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (11) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (12) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (13) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (14) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; School of Life Science, Chongqing University, Chongqing, China. (15) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China. (16) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (17) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (18) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (19) TCRCure Biopharma, Durham, NC, USA. (20) Department of Radiology and Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA. (21) Department of Radiology and Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA. (22) Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Hill, NC, USA. (23) Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. (24) Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. (25) Department of Immunology, Duke University Medical Center, Durham, NC, USA. Electronic address: qi-jing.li@duke.edu. (26) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China. Electronic address: bo.zhu@tmmu.edu.cn.
