SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint.
Emma HajajGalit EisenbergShiri KleinShoshana FrankenburgSharon MerimsInna Ben DavidThomas M EisenhaureSarah E HenricksonAlexandra Chloé VillaniNir HacohenNathalie AbudiRinat AbramovichJonathan E CohenTamar PeretzAndre VeilletteMichal LotemPublished in: eLife (2020)
SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 -/- mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 -/- CD8+ T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1 x SLAMF6 -/- cells, and upon activation, they acquired an effector-memory phenotype. Adoptive transfer of Pmel-1 x SLAMF6 -/- T cells to melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. LAG-3 expression was elevated in the SLAMF6 -/- cells, and the addition of the LAG-3-blocking antibody to the adoptive transfer protocol improved the SLAMF6 -/- T cells and expedited the antitumor response even further. The results from this study support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8+ T cells to eradicate tumors.
Keyphrases
- induced apoptosis
- transcription factor
- poor prognosis
- regulatory t cells
- cell therapy
- high fat diet induced
- randomized controlled trial
- cell cycle arrest
- magnetic resonance
- dendritic cells
- stem cells
- adipose tissue
- cell cycle
- metabolic syndrome
- cell proliferation
- endoplasmic reticulum stress
- cell death
- wild type
- insulin resistance
- heart rate
- density functional theory
- basal cell carcinoma