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

• 成果类型: Article
• 署名作者: LaMarche, Nelson M.; Hegde, Samarth; Park, Matthew D.; Maier, Barbara B.; Troncoso, Leanna; Le Berichel, Jessica; Hamon, Pauline; Belabed, Meriem; Mattiuz, Raphael; Hennequin, Clotilde; Chin, Theodore; Reid, Amanda M.; Reyes-Torres, Ivan; 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; Passegue, Emmanuelle; Kim-Schulze, Seunghee; Brown, Brian D.; Hirsch, Fred R.; Kim, Brian S.; Marron, Thomas U.; Merad, Miriam
• 署名单位: Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Columbia University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Agency for Science Technology & Research (A*STAR); A*STAR - Singapore Immunology Network (SIgN); Institut National de la Sante et de la Recherche Medicale (Inserm); UNICANCER; Gustave Roussy; Universite Paris Saclay; Chinese Academy of Sciences; Shanghai Jiao Tong University; Icahn School of Medicine at Mount Sinai; Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU); Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Austrian Academy of Sciences; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5098
• DOI: 10.1038/s41586-023-06797-9
• 发表日期: 2024-01-04
• 页码: 166-+
• 关键词: survival; cells; macrophages; landscape; monocytes; DYNAMICS; STATES

摘要

Myeloid cells are known to suppress antitumour immunity(1). 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-4R alpha in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4R alpha 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-4R alpha blocking antibody dupilumab(2-5) 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. Single-cell transcriptomics studies on human and mouse non-small cell lung cancer and conditional knockout mouse models show that IL-4 from bone marrow basophils drives the development of granulocyte-monocyte progenitors to myeloid cells that suppress antitumour immunity.