An Il4 Signalling Axis In Bone Marrow Drives Protumorigenic Myelopoiesis Nelson M Lamarche1 by Nelson M. Lamarche1, 2, 3, Samarth Hegde1, 2, 3, 18, Matthew D. Park1, 2, 3, 18, Barbara B. Maier1, 2, 3, 17, 101038/S41586023067979 instant download after payment.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defned. 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-infltrating 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 efect. 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 identifer NCT05013450). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defnes a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifes 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.