| First Author | LaMarche NM | Year | 2024 |
| Journal | Nature | Volume | 625 |
| Issue | 7993 | Pages | 166-174 |
| PubMed ID | 38057662 | Mgi Jnum | J:354880 |
| Mgi Id | MGI:7660360 | Doi | 10.1038/s41586-023-06797-9 |
| Citation | LaMarche NM, et al. (2024) An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 625(7993):166-174 |
| abstractText | 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-4Ralpha in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Ralpha 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-4Ralpha 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. |
