A conserved dendritic-cell regulatory program limits antitumour immunity

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 and Miriam Merad ()
Additional contact information
Barbara Maier: Icahn School of Medicine at Mount Sinai
Andrew M. Leader: Icahn School of Medicine at Mount Sinai
Steven T. Chen: Icahn School of Medicine at Mount Sinai
Navpreet Tung: Icahn School of Medicine at Mount Sinai
Christie Chang: Icahn School of Medicine at Mount Sinai
Jessica LeBerichel: Icahn School of Medicine at Mount Sinai
Aleksey Chudnovskiy: Icahn School of Medicine at Mount Sinai
Shrisha Maskey: Icahn School of Medicine at Mount Sinai
Laura Walker: Icahn School of Medicine at Mount Sinai
John P. Finnigan: Icahn School of Medicine at Mount Sinai
Margaret E. Kirkling: New York University School of Medicine
Boris Reizis: New York University School of Medicine
Sourav Ghosh: Yale University School of Medicine
Natalie Roy D’Amore: Immuno-oncology Drug Discovery Unit, Takeda Oncology
Nina Bhardwaj: Icahn School of Medicine at Mount Sinai
Carla V. Rothlin: Yale University School of Medicine
Andrea Wolf: Icahn School of Medicine at Mount Sinai
Raja Flores: Icahn School of Medicine at Mount Sinai
Thomas Marron: Icahn School of Medicine at Mount Sinai
Adeeb H. Rahman: Icahn School of Medicine at Mount Sinai
Ephraim Kenigsberg: Icahn School of Medicine at Mount Sinai
Brian D. Brown: Icahn School of Medicine at Mount Sinai
Miriam Merad: Icahn School of Medicine at Mount Sinai

Nature, 2020, vol. 580, issue 7802, 257-262

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2134-y

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