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.
Subject(s)
Bone Marrow , Carcinogenesis , Interleukin-4 , Myelopoiesis , Signal Transduction , Animals , Humans , Mice , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Bone Marrow/drug effects , Bone Marrow/metabolism , 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-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Immune Checkpoint Inhibitors/immunology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Interleukin-4/metabolism , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Monocytes/drug effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Recurrence , Signal Transduction/drug effectsABSTRACT
Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.
ABSTRACT
Sagging of the periumbilical skin, also known as the "sad umbilicus," is one of the most common postoperative complications in liposuction. It is characterized by an increase in the width and decrease in the height of the umbilicus. Technological advances in power-assisted liposuction resulting in skin tightening have been central to improvements in the treatment of sagging skin. Laser-assisted liposuction is a procedure in which a laser fiber induces lipolysis and skin tightening. Laser treatment delivered using a 980-nm diode laser may result in up to 30% skin surface area contraction. The aim of this study was to describe a new technique called the "happy protocol" for the treatment and prevention of the sad umbilicus. The periumbilical region is treated using a 980-nm diode laser set to an output power of 20 W, with a total delivered energy of 5000 J. The developed technique may be applied to correct shape distortions or to create a natural-looking and aesthetically pleasant umbilicus during liposuction. A decrease in the width of the umbilicus followed by an increase in height are observed in the first postoperative days. Patients who were followed up for 7 months postoperatively showed positive aesthetic results. The final outcome was an oval-shaped umbilicus, with increased height and reduced sagging in the periumbilical region.