A conserved dendritic-cell regulatory program limits antitumour immunity

Authors list

Barbara Maier Andrew M Leader Steven T Chen Navpreet Tung Christie Chang Jessica LeBerichel Aleksey Chudnovskiy Shrisha Maskey Laura Walker John P Finnigan Margaret E Kirkling Boris Reizis Sourav Ghosh Natalie Roy D'Amore Nina Bhardwaj Carla V Rothlin Andrea Wolf Raja Flores Thomas Marron Adeeb H Rahman Ephraim Kenigsberg Brian D Brown Miriam Merad
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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 cells1-3. 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-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.

Journal details

Journal Nature
Volume 580
Issue number 7802
Pages 257-262
Available online
Publication date

Full text links

Publisher website (DOI) 10.1038/s41586-020-2134-y
Europe PubMed Central 32269339
Pubmed 32269339

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