Journal Article

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

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

2024

Overview

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-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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 38/91 / 631/250/232/2059 / 631/250/251 / 631/250/580 / 64/60 / 96/106 / Animals / Antibodies / Antibodies, Monoclonal, Humanized / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - metabolism / Blocking antibodies / Bone marrow / Bone Marrow - drug effects / Bone Marrow - metabolism / Cancer / Carcinogenesis - drug effects / Carcinogenesis - metabolism / Carcinogenesis - pathology / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - metabolism / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Non-Small-Cell Lung - therapy / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Cytokines / Cytotoxicity / Deletion / Dendritic cells / Eosinophils / Gene sequencing / Genes / Granulocytes / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - immunology / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Interleukin 4 / Interleukin-4 - metabolism / Interleukin-4 Receptor alpha Subunit / Leukocytes (basophilic) / Leukocytes (eosinophilic) / Leukocytes (granulocytic) / Lung cancer / Lung diseases / Lung Neoplasms - immunology / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Lung Neoplasms - therapy / Lungs / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Macrophages / Mice / Monoclonal antibodies / Monocytes / Monocytes - drug effects / multidisciplinary / Myeloid cells / Myelopoiesis / Neutrophils / Non-small cell lung carcinoma / Osteoprogenitor cells / Patients / PD-1 protein / PD-L1 protein / Phenotypes / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - metabolism / Recurrence / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Small cell lung carcinoma / Tumors