Using scRNAseq, Maier and Leader et al. identified a novel dendritic cell subgroup (mregDCs) characterized by coordinated regulation of expression of maturation (Cd40, Ccr7, and Il12b), regulatory (Cd274, Pdcd1lg2, and Cd200), and migration (Ccr7, Fscn1, and ADAM8) markers in human and mouse normal lung and NSCLC. Tumor antigens uptake by DC1 induced the mregDC program, leading to AXL-mediated PD-L1 upregulation and an increase in IL-4 levels, which negatively regulated IL-12 production. IL-4 blockade enhanced IL-12 production by mregDCs, increased effector T cell infiltration, and reduced tumor burden.
Contributed by Shishir Pant
ABSTRACT: Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8(+) T cells(1-3). Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name 'mature DCs enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein-a key checkpoint molecule-in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-gamma and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.
Author Info: (1) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, N
Author Info: (1) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. (8) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Department of Pathology and Department of Medicine, New York University School of Medicine, New York, NY, USA. Graduate Program in Genetics and Development, Columbia University Medical Center, New York, NY, USA. (12) Department of Pathology and Department of Medicine, New York University School of Medicine, New York, NY, USA. (13) Department of Neurology & Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA. (14) Immuno-oncology Drug Discovery Unit, Takeda Oncology, Cambridge, MA, USA. (15) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (16) Department of Immunobiology & Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA. (17) Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (18) Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (21) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (22) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (23) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu.
