A Natural Killer/Dendritic Cell Axis Defines Responsive Tumor Microenvironments in Melanoma

By Kevin C. Barry, Joy Hsu, Miranda L. Broz, F. J. Cueto, M. Binnewies, A. Combes, Amanda E. Nelson, K. Loo, Raj Kumar, M. Rosenblum and 12 more. Nature Medicine, 2018

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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. Cross-talk between innate immune cells helps to enhance the antitumor T cell response during checkpoint blockade therapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a22bcbeedc1602b99353d98c0e2c5ead63318418

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Citations in the corpus

Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, background): “The PD-1 pathway is a key mediator of local immunosuppression in the tumor microenvironment (TME).”
Advances in immunotherapy for hepatocellular carcinoma (2021, background): “I.M. receives funding from MINECO SAF2014-52361-R and SAF 2017- 83267-C2-1R; Worldwide Cancer Research Grant (15-1146); the Asociacion Española Contra el Cancer (AECC) Foundation under grant GCB15152947MELE; and the European Union’s Horizon 2020 Program (grant agreement no. 635122 PROCROP).”