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 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 Veluswamy, Nicole 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 and Miriam Merad ()
Additional contact information
Nelson M. LaMarche: Icahn School of Medicine at Mount Sinai
Samarth Hegde: Icahn School of Medicine at Mount Sinai
Matthew D. Park: Icahn School of Medicine at Mount Sinai
Barbara B. Maier: Icahn School of Medicine at Mount Sinai
Leanna Troncoso: Icahn School of Medicine at Mount Sinai
Jessica Berichel: Icahn School of Medicine at Mount Sinai
Pauline Hamon: Icahn School of Medicine at Mount Sinai
Meriem Belabed: Icahn School of Medicine at Mount Sinai
Raphaël Mattiuz: Icahn School of Medicine at Mount Sinai
Clotilde Hennequin: Icahn School of Medicine at Mount Sinai
Theodore Chin: Icahn School of Medicine at Mount Sinai
Amanda M. Reid: Icahn School of Medicine at Mount Sinai
Iván Reyes-Torres: Icahn School of Medicine at Mount Sinai
Erika Nemeth: Icahn School of Medicine at Mount Sinai
Ruiyuan Zhang: Columbia University
Oakley C. Olson: Columbia University
Deborah B. Doroshow: Icahn School of Medicine at Mount Sinai
Nicholas C. Rohs: Icahn School of Medicine at Mount Sinai
Jorge E. Gomez: Icahn School of Medicine at Mount Sinai
Rajwanth Veluswamy: Icahn School of Medicine at Mount Sinai
Nicole Hall: Icahn School of Medicine at Mount Sinai
Nicholas Venturini: Icahn School of Medicine at Mount Sinai
Florent Ginhoux: BIOPOLIS
Zhaoyuan Liu: Shanghai Jiao Tong University School of Medicine
Mark Buckup: Icahn School of Medicine at Mount Sinai
Igor Figueiredo: Icahn School of Medicine at Mount Sinai
Vladimir Roudko: Icahn School of Medicine at Mount Sinai
Kensuke Miyake: Tokyo Medical and Dental University (TMDU)
Hajime Karasuyama: Tokyo Medical and Dental University (TMDU)
Edgar Gonzalez-Kozlova: Icahn School of Medicine at Mount Sinai
Sacha Gnjatic: Icahn School of Medicine at Mount Sinai
Emmanuelle Passegué: Columbia University
Seunghee Kim-Schulze: Icahn School of Medicine at Mount Sinai
Brian D. Brown: Icahn School of Medicine at Mount Sinai
Fred R. Hirsch: Icahn School of Medicine at Mount Sinai
Brian S. Kim: Icahn School of Medicine at Mount Sinai
Thomas U. Marron: Icahn School of Medicine at Mount Sinai
Miriam Merad: Icahn School of Medicine at Mount Sinai

Nature, 2024, vol. 625, issue 7993, 166-174

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-023-06797-9

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