Year: 2025
Type: article
Abstract: Description Immunotherapies, like immune checkpoint inhibitors, are transforming cancer treatment, yet many patients do not respond effectively. Thus, understanding the tumor microenvironment (TME) features that enhance patient responses is crucial. Our previous work demonstrated that an innate immune axis—where natural killer (NK) cells aid type 1 conventional dendritic cells (cDC1s) through the cDC1-promoting cytokine FMS-like tyrosine kinase 3 ligand (Flt3L)—is associated with improved patient survival and predicts ICI responsiveness in melanoma. Preliminary findings indicate that treating NK cells ex vivo with IL-15 increases Flt3L levels, but the impact of enhanced Flt3L production by NK cells within the TME remains unexplored. To investigate this, we engineered the B16F10 melanoma line to express IL-15 (B16F10-IL-15) and assessed how elevated IL-15 in the TME affects Flt3L expression and cDC1 populations. In vitro analysis verified that B16F10-IL-15 cells produce IL-15. Using in vivo models, we tracked Flt3L production by NK cells and analyzed the immune response in the B16F10-IL-15 TME. Our results show that IL-15 expression correlates with increased NK cells, CD8+ T cells, and cDC1s, notably a threefold increase in cDC1s. This indicates that IL-15 modulates the NK cell-cDC1 axis in vivo, highlighting a characteristic of NK cells that could enhance ICI treatment strategies and inform future NK cell-centered therapies. Funding Sources This work is funded by the Bowl-A-Noma Foundation and grants from Melanoma Research Alliance and American Cancer Society. The Summer Undergraduate Research Program is supported in parts by the Fred Hutch Internship Program and individual labs/research groups. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Source: The Journal of Immunology
Institution: Fred Hutch Cancer Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416446388
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