ABSTRACT
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 Statement
The authors have declared no competing interest.
Footnotes
Financial support: The work of E.H., E.Z., S.T., G.E., S.K., S.F., S.M., J.C., and M.L. was supported by research grants from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), the Canadian Institutes of Health Research (CIHR), Melanoma Research Alliance (MRA), the Israel Cancer Research Fund (ICRF), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF), the Azrieli Foundation, Deutsche Forschungsgemeinschaft (DFG); the Rosetrees Trust and the Perlstein Family Fund;