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SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a new T cell checkpoint

By Emma Hajaj, Galit Eisenberg, Shiri Klein, Shoshana Frankenburg, Sharon Merims, Inna Ben-David, Thomas Eisenhaure, Sarah E. Henrickson, Alexandra-Chloé Villani, Nir Hacohen, Nathalie Abudi, Rinat Abramovich, Jonathan Cohen, Tamar Peretz, André Veillette, Michal Lotem

Posted 31 Oct 2019
bioRxiv DOI: 10.1101/824946 (published DOI: 10.7554/eLife.52539)

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 KO mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 KO CD8 T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1xSLAMF6 KO cells, and upon activation, they acquired an effector-memory phenotype. Blocking LAG-3 improved the function of SLAMF6 deficient T cells even further. Finally, adoptive transfer of Pmel-1xSLAMF6 KO T cells into melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. These results support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8 T cells to eradicate tumors.

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