LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T cell responses

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en s'exprimant sur la surface des cellules de mélanome, une protéine (LSCEtin) favorise l'échappement à la réponse immune et la progression tumorale

Résumé en anglais

Co-inhibitory molecules of T cell immune responses have received considerable attention for their successful clinical effects during immunotherapy for the treatment of multiple cancers. LSECtin, a cell-surface member of the C-type lectin DC-SIGN family, has been shown to inhibit T cell responses and viral clearance in the liver. However, its role in antitumor immunity and tumor growth remains unclear. Herein, we detected LSECtin expression in approximately 50% of melanoma samples in a human tumor tissue array. In a B16 melanoma model, we revealed that LSECtin, when expressed on B16 cells, promoted tumor growth and LSECtin blockade resulted in significantly slower tumor growth in both WT and LSECtin KO mice; this LSECtin-mediated tumor-promoting effect was abrogated in Rag1-/- mice or in response to CD4+ or CD8+ T cell depletion. We further determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating cell cycle-regulating kinases such as CDK2, CDK4, and CDK6. Consistently, LSECtin expressed on B16 tumor cells inhibited tumor-specific T cell responses in vivo and in vitro. Importantly, we indicated that LSECtin interacted with LAG-3, and LAG-3 blockade restored the reduced IFN-γ secretion mediated by melanoma-derived LSECtin. Together, LSECtin expressed on melanoma cells appears to be a novel possible mechanism of immune escape of melanoma cells and provides a foundation for potential combinatorial immunotherapy strategies.