학술논문
An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis
Document Type
Article
Author
LaMarche, Nelson M.; Hegde, Samarth; Park, Matthew D.; Maier, Barbara B.; Troncoso, Leanna; Le Berichel, Jessica; Hamon, Pauline; Belabed, Meriem; Mattiuz, Raphaël; Hennequin, Clotilde; Chin, Theodore; Reid, Amanda M.; Reyes-Torres, Iván; 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; Passegué, Emmanuelle; Kim-Schulze, Seunghee; Brown, Brian D.; Hirsch, Fred R.; Kim, Brian S.; Marron, Thomas U.; Merad, Miriam
Source
Nature; January 2024, Vol. 625 Issue: 7993 p166-174, 9p
Subject
Language
ISSN
00280836; 14764687
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 dupilumab2–5given 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.