Journal Article

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

Barry, Kevin C., Combes, Alexis J., Rosenblum, Michael D., Nelson, Amanda E., Krummel, Matthew F., Wolf, Denise M., Bhardwaj, Nina, Ha, Patrick K., Pollack, Joshua L., Broz, Miranda L., Cueto, Francisco J., Chan, Vincent, Asthana, Saurabh, Alvarado, Michael D., Daud, Adil I., Loo, Kimberly, Hsu, Joy, Samad, Bushra, Kumar, Raj, Bogunovic, Dusan, Binnewies, Mikhail, Ryan, William R.

2018

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/251 / 631/67/327 / 692/308/53 / 692/308/575 / 692/699/67/580 / Abundance / Antigens, Surface - metabolism / B cells / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Care and treatment / Cell Communication / Cell Survival / Cytokines / Cytotoxicity / Dendritic cells / Dendritic Cells - immunology / FLT3L protein / Gene expression / Genes / Health aspects / Human behavior / Humans / Immune response / Immunotherapy / Infectious Diseases / Killer cells / Killer Cells, Natural - immunology / Lymphocytes / Lymphocytes - metabolism / Lymphocytes T / Medical schools / Melanoma / Melanoma - immunology / Melanoma - pathology / Membrane Proteins - metabolism / Metabolic Diseases / Microenvironments / Molecular Medicine / Natural killer cells / Neurosciences / PD-1 protein / Survival Analysis / T cell receptors / T cells / Thrombomodulin / Tumor Microenvironment - immunology / Tumors