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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We thank L. Lanier, J. Roose and L. Fong for advice, and we thank M. Spasic and N. Khurana for support with response data. This work was supported by National Institutes of Health (NIH) grant R01CA197363, awarded to M.F.K. Acquisition and processing of human melanoma samples in cohort A described in this study was funded in part by contributions from AbbVie, Amgen, and Bristol-Myers Squibb as members of the Immunoprofiler Consortium. Further support came from NIH grant 5P30CA082103, awarded to the University of California, San Francisco (UCSF) Hellen Diller Family Comprehensive Cancer Center. M.B. was supported by the Genentech Predoctoral Research Fellowship, the Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award, and the Achievement Reward for College Scientists Scholarship. K.C.B. was supported by a postdoctoral fellowship from the Cancer Research Institute and Fibrolamellar Cancer Foundation.
J.L.P. was an employee at Pionyr Immunotherapeutics at the time of manuscript writing. The other authors declare no competing interests.
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Barry, K.C., Hsu, J., Broz, M.L. et al. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat Med 24, 1178–1191 (2018). https://doi.org/10.1038/s41591-018-0085-8
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