| RRC ID |
86958
|
| Author |
Avanessian SC, van den Bijgaart RJE, Chew NW, Supper VM, Tang TT, Zhang Y, Zhao YQ, Abe K, Gauthier J, Barry KC.
|
| Title |
IL2/IL15 Signaling Induces NK Cell Production of FLT3LG, Augmenting Anti-PD-1 Immunotherapy.
|
| Journal |
Cancer Immunol Res
|
| Abstract |
NK cells play a critical role in anticancer immunity through their direct cytotoxicity and production of cytokines, such as FMS-like tyrosine kinase 3 ligand (Flt3L). NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. In this study, we show that NK cell production of Flt3l in the tumor is regulated by activation and that activation by IL2 and IL15 uniquely induced Flt3L expression in NK cells. In melanoma, IL2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti-PD-1 immunotherapy response. Furthermore, NK cell subsets differentially regulated Flt3l in the tumor, with CD11b-CD27+ NK cells in mouse tumors enriched for IL2 family signaling and upregulating Flt3l upon activation. Consistently, human CD56brightCD16- NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.
|
| Volume |
14(1)
|
| Pages |
122-138
|
| Published |
2026-1-8
|
| DOI |
10.1158/2326-6066.CIR-24-1259
|
| PII |
766182
|
| PMID |
41081432
|
| PMC |
PMC12582536
|
| MeSH |
Animals
Cell Line, Tumor
Dendritic Cells / immunology
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immunotherapy / methods
Interleukin-15* / immunology
Interleukin-15* / metabolism
Interleukin-2* / immunology
Interleukin-2* / metabolism
Killer Cells, Natural* / immunology
Killer Cells, Natural* / metabolism
Melanoma* / immunology
Melanoma* / pathology
Melanoma* / therapy
Membrane Proteins* / immunology
Membrane Proteins* / metabolism
Mice
Mice, Inbred C57BL
Programmed Cell Death 1 Receptor* / antagonists & inhibitors
Programmed Cell Death 1 Receptor* / immunology
Signal Transduction / immunology
|
| IF |
8.728
|
| Resource |
| Mice |
RBRC09486 |
