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

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Pages (from-to)166-174
Number of pages9
JournalNature
Volume625
Issue number7993
DOIs
StatePublished - 4 Jan 2024

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