Natural Killer Cells Enhance Immune Checkpoint Blockade Efficacy

Immune checkpoint blockade can reactivate antitumor T-cell responses to provide clinical benefit in patients with a variety of tumor types. However, the majority of patients do not respond, and the effect of other immune cell types on the response to immune checkpoint blockade has not been well characterized. A subset of BDCA-3⁺ intratumor stimulatory dendritic cells (SDC) were shown to be required for adoptive T-cell therapy in mouse models, and are associated with poor outcomes in WNT–β-catenin–mutant melanoma. Barry and colleagues investigated the role of these SDCs in response to immune checkpoint blockade patients with melanoma. Higher levels of SDCs were associated with extended overall survival and a higher rate of response to immune checkpoint blockade with an anti–PD-1 antibody, and upregulation of the gene encoding the cytokine FLT3LG within the tumor was associated with increased SDC frequency in melanoma. FLT3LG was produced by lymphocytes, most notably natural killer (NK) cells, in the tumor microenvironment and was required to maintain intratumoral SDC levels. Further, NK cells formed frequent, stable interactions with SDCs in the tumor microenvironment. Analysis of data from The Cancer Genome Atlas revealed that NK-cell abundance was associated with increased FLT3LG expression and SDC abundance in human melanoma, as well as other tumor types, and, in patients with melanoma, abundant NK cells were associated with increased overall survival and increased responsiveness to anti–PD-1 immunotherapy. Collectively, these findings indicate that NK cell frequency and SDC–NK cell clusters may be associated with response to immune checkpoint blockade, and suggest the possibility for therapies aimed at recruiting and activating NK cells in the tumor to enhance the efficacy of immune checkpoint blockade.

Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat Med 2018 Jun 25 [Epub ahead of print].

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