Abstract A042: Common gamma-chain signaling in NK cells promotes their Flt3L-dependent support of cDC1s in melanoma

Abstract Natural killer (NK) cells are an innate lymphocyte population that have an inherent ability to recognize and eliminate malignant cells without requiring prior sensitization. However, NK cells are more than just a population of killers—they are prominent producers of cytokines and chemokines, lending them a pivotal ability to orchestrate robust immune responses involving other immune cell types. We have previously shown that NK cells in the tumor microenvironment (TME) are critical regulators of type one conventional dendritic cells (cDC1s), which are required for protective immune responses against cancer and for the success of checkpoint blockade immunotherapies. Through the production of the cDC1-formative cytokine FMS-like tyrosine kinase 3 ligand (Flt3l/Flt3L in mice or FLT3LG/FLT3LG in humans), NK cells support cDC1 abundance in the melanoma TME. Indeed, the abundance of this innate immune axis of NK cells-FLT3LG-cDC1s defines checkpoint blockade-responsiveness in melanoma patients. Despite this clear clinical relevance, the molecular and cellular mechanisms underlying NK cell regulation of FLT3LG are not understood. Here, we investigated signals that modulate NK cell activity and found that the common gamma- chain cytokines IL-2 and IL-15 are uniquely able to upregulate Flt3L production by NK cells, and that treatment of NK cells with IL-2 and IL-15 led to increased support of cDC1s both in-vitro and in-vivo. This local NK cell support of cDC1s in the TME, in combination with checkpoint blockade, potentiates tumor control in the non-responsive B16F10 melanoma model. Furthermore, we demonstrated that a particular subset of immunomodulatory NK cells that excels in cytokine production is primarily responsible for the production of Flt3L in response to common gamma-chain signaling. By analyzing human melanoma patient datasets, we found that the abundance of immunomodulatory NK cells within the TME correlates both with FLT3LG and cDC1 abundance. These findings define the features of the TME and of NK cells that promote successful cancer responses and will inform future NK cell-based therapy approaches. Citation Format: Shayan C Avanessian, Renske J.E. van den Bijgaart, Nayvin W Chew, Thao T Tang, Kevin C Barry. Common gamma-chain signaling in NK cells promotes their Flt3L-dependent support of cDC1s in melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A042.