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Nat Med. 2018 Aug;24(8):1178-1191. doi: 10.1038/s41591-018-0085-8. Epub 2018 Jun 25.

A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments.

Author information

1
Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
2
UCSF Immunoprofiler Initiative, University of California San Francisco, San Francisco, CA, USA.
3
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
4
Department of Biochemistry, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
5
Melanoma Clinical Research Unit, University of California San Francisco, San Francisco, CA, USA.
6
Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
7
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
8
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10
Department of Otolaryngology, University of California San Francisco, San Francisco, CA, USA.
11
Pionyr Immunotherapeutics, San Francisco, CA, USA.
12
Department of Pathology, University of California San Francisco, San Francisco, CA, USA. matthew.krummel@ucsf.edu.
13
UCSF Immunoprofiler Initiative, University of California San Francisco, San Francisco, CA, USA. matthew.krummel@ucsf.edu.

Abstract

Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.

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PMID:
29942093
PMCID:
PMC6475503
DOI:
10.1038/s41591-018-0085-8
[Indexed for MEDLINE]
Free PMC Article

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