A conserved dendritic-cell regulatory program limits antitumour immunity

• Published in: Nature (London) Vol. 580; no. 7802; pp. 257 - 262
• Main Authors: Maier, Barbara, Leader, Andrew M., Chen, Steven T., Tung, Navpreet, Chang, Christie, LeBerichel, Jessica, Chudnovskiy, Aleksey, Maskey, Shrisha, Walker, Laura, Finnigan, John P., Kirkling, Margaret E., Reizis, Boris, Ghosh, Sourav, D’Amore, Natalie Roy, Bhardwaj, Nina, Rothlin, Carla V., Wolf, Andrea, Flores, Raja, Marron, Thomas, Rahman, Adeeb H., Kenigsberg, Ephraim, Brown, Brian D., Merad, Miriam
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2020; Nature Publishing Group
• Subjects: 13/1; 13/31; 14/19; 38/91; 631/250/251; 631/250/580; 64/60; Analysis; Animals; Antigens; Antigens, Neoplasm - immunology; Antimitotic agents; Antineoplastic agents; Apoptosis; Axl protein; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Cancer; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; CC chemokine receptors; CCR7 protein; CD200 antigen; CD40 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell adhesion & migration; Control; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Dendritic structure; Effector cells; Gene sequencing; Genes; Humanities and Social Sciences; Humans; Immune checkpoint; Immunity; Immunity (Disease); Immunoregulation; Immunotherapy; Interferon; Interferon-gamma - immunology; Interleukin 1; Interleukin-12 - immunology; Interleukin-4 - antagonists & inhibitors; Interleukin-4 - immunology; Interleukin-4 - metabolism; Kinases; Ligands; Lung cancer; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lungs; Lymphatic system; Lymphocytes; Lymphocytes T; Male; Metastasis; Mice; multidisciplinary; Protein-tyrosine kinase receptors; Proteins; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Tumor Burden - drug effects; Tumor Burden - immunology; Tumor necrosis factor-TNF; Tumors; Tyrosine; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-020-2134-y

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 ( C d40 , C cr7 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-γ 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. After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.