PDF(Pubmed)
Abstract：
Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.
摘要：
已知髓样细胞抑制抗肿瘤免疫1。然而,免疫抑制性骨髓细胞状态的分子驱动因素尚不明确.在这里，我们使用人和小鼠非小细胞肺癌（NSCLC）病变的单细胞RNA测序，并发现在这两个物种中，2型细胞因子白介素4（IL-4）被预测为肿瘤浸润性单核细胞衍生的巨噬细胞表型的主要驱动因素。使用一组条件敲除小鼠，我们发现，只有在骨髓早期骨髓祖细胞中IL-4受体IL-4Rα的缺失降低了肿瘤负荷，而下游成熟骨髓细胞中IL-4Rα的缺失没有影响。机械上,源自骨髓嗜碱性粒细胞和嗜酸性粒细胞的IL-4作用于粒细胞-单核细胞祖细胞，以转录地编程免疫抑制性肿瘤促进骨髓细胞的发育。因此，嗜碱性粒细胞的消耗极大地减少了肿瘤负担和正常的骨髓生成。随后，我们启动了一项IL-4Rα阻断抗体dupilumab2-5联合PD-1/PD-L1检查点阻断的临床试验，用于单独使用PD-1/PD-L1阻断的复发性或难治性NSCLC患者（ClinicalTrials.gov标识符NCT05013450）。Dupilumab补充减少循环单核细胞，扩增的肿瘤浸润性CD8T细胞，六分之一的病人，治疗后两个月，临床反应接近完全。我们的研究定义了IL-4在控制癌症免疫抑制性骨髓生成中的核心作用。确定了一种用于人类免疫检查点阻断的新型联合疗法，并强调癌症是一种全身性疾病，需要超出原发疾病部位的治疗策略。
