Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy
Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy
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DOI：
10.1016/j.ccell.2022.04.018
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发表时间：
2022-06-13
期刊：
影响因子：
50.3
通讯作者：
Zhu, Bo
中科院分区：
文献类型：
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作者：
Long, Haixia;Jia, Qingzhu;Zhu, Bo
尽管免疫检查点抑制剂(ICIS)在抗癌治疗方面取得了前所未有的成功，但临床上仍然需要确定ICI治疗效果和潜在耐药性的额外机制。在这里，通过对癌症患者和荷瘤小鼠的谱系追踪，我们证明了红系祖细胞失去了它们的发育潜力，并转换为髓系。单细胞转录组分析表明，尽管红系基因的表达在数量上存在差异，但红系分化的髓系细胞(EDMC)在转录上与其髓系起源的细胞没有区别。EDMC具有多方面的机制来抑制T细胞介导的抗肿瘤反应。因此，在大多数实体癌中，肿瘤组织中的EDMC含量与T细胞炎症呈负相关；此外，根据贫血的表现，EDMC的丰富预示着接受ICI治疗的不同队列患者的不良预后。总之，我们的发现揭示了一种前馈机制，肿瘤通过该机制利用贫血触发的红细胞生成来进行髓系转分化和免疫抑制。
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.