RT Journal Article
SR Electronic
T1 Alternative splicing of SLAMF6 in human T cells creates a co-stimulatory isoform that counteracts the inhibitory effect of the full-length receptor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.21.262238
DO 10.1101/2020.08.21.262238
A1 Emma Hajaj
A1 Elad Zisman
A1 Shay Tzaban
A1 Sharon Merims
A1 Jonathan Cohen
A1 Shiri Klein
A1 Shoshana Frankenburg
A1 Moshe Sade-Feldman
A1 Yuval Tabach
A1 Keren Yizhak
A1 Ami Navon
A1 Polina Stepensky
A1 Nir Hacohen
A1 Tamar Peretz
A1 André Veillette
A1 Rotem Karni
A1 Galit Eisenberg
A1 Michal Lotem
YR 2020
UL http://biorxiv.org/content/early/2020/08/22/2020.08.21.262238.abstract
AB SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor exhausted T cells. In humans, SLAMF6 has three splice isoforms involving its V-domain. While the canonical 8-exon receptor inhibits T cell activation through SAP recruitment, the short isoform SLAMF6Δ17-65 has a strong agonistic effect. The costimulatory action depends on protein phosphatase SHP-1 and leads to a cytotoxic molecular profile governed by transcription factors Tbet, Runx3, and Tcf7. In T cells from individual patients treated with immune checkpoint blockade, a shift was noted towards SLAMF6Δ17-65. Splice-switching antisense oligonucleotides designed to target the SLAMF6 splice junction, enhanced SLAMF6Δ17-65 in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The possible emergence of two opposing isoforms from the SLAMF6 gene may represent an immune-modulatory mechanism that can be exploited for cancer immunotherapy.Competing Interest StatementThe authors have declared no competing interest.