小柯机器人

美国西奈山伊坎医学院Miriam Merad团队发现，骨髓中的IL-4信号轴驱动促瘤性骨髓生成。2023年12月6日，《自然》杂志在线发表了这项成果。

研究人员使用了人类和小鼠非小细胞肺癌（NSCLC）病变的单细胞RNA测序，发现在这两种物种中，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源性巨噬细胞表型的主要驱动因素。通过一组条件敲除小鼠，研究人员发现仅在骨髓中删除早期髓系祖细胞中的IL-4受体IL-4Rα可减少肿瘤负荷，而在下游成熟髓系细胞中删除IL-4Rα则没有效果。从机制上讲，来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，通过转录编程促进免疫抑制肿瘤的骨髓细胞的发育。因此，嗜碱性细胞的消耗大大减少了肿瘤负荷和正常化的骨髓生成。

随后，研究人员启动了一项临床试验，将IL-4Rα阻断抗体dupilumab与PD-1/PD-L1检查点阻断联合给药，用于单独使用PD-1/PD-L1阻断的复发或难治性NSCLC患者（ClinicalTrials.gov标识符NCT05013450）。补充dupilumab减少了循环单核细胞，扩大了肿瘤浸润的CD8 T细胞，并且在六分之一的患者中，在治疗两个月后驱动了近乎完全的临床反应。这项研究确定了IL-4在控制癌症免疫抑制性骨髓生成中的核心作用，确定了一种新的人类免疫检查点阻断联合疗法，并强调了癌症作为一种系统性疾病需要超越原发部位的治疗策略。

据了解，骨髓细胞被认为可以抑制抗肿瘤免疫。然而，免疫抑制骨髓细胞状态的分子驱动因素还没有很好地定义。

附：英文原文

Title: An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis

Author: LaMarche, Nelson M., Hegde, Samarth, Park, Matthew D., Maier, Barbara B., Troncoso, Leanna, Le Berichel, Jessica, Hamon, Pauline, Belabed, Meriem, Mattiuz, Raphal, Hennequin, Clotilde, Chin, Theodore, Reid, Amanda M., Reyes-Torres, Ivn, Nemeth, Erika, Zhang, Ruiyuan, Olson, Oakley C., Doroshow, Deborah B., Rohs, Nicholas C., Gomez, Jorge E., Veluswamy, Rajwanth, Hall, Nicole, Venturini, Nicholas, Ginhoux, Florent, Liu, Zhaoyuan, Buckup, Mark, Figueiredo, Igor, Roudko, Vladimir, Miyake, Kensuke, Karasuyama, Hajime, Gonzalez-Kozlova, Edgar, Gnjatic, Sacha, Passegu, Emmanuelle, Kim-Schulze, Seunghee, Brown, Brian D., Hirsch, Fred R., Kim, Brian S., Marron, Thomas U., Merad, Miriam

Issue&Volume: 2023-12-06

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 dupilumab2,3,4,5 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.

DOI: 10.1038/s41586-023-06797-9

Source: https://www.nature.com/articles/s41586-023-06797-9

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