Alternative splicing of the inhibitory immune checkpoint receptor SLAMF6 generates a dominant positive form, boosting T-cell effector functions

Emma Hajaj, Elad Zisman, Shay Tzaban, Sharon Merims, Cohen Jonathan, Shiri Klein, Shoshana Frankenburg, Moshe Sade-Feldman, Yuval Tabach, Keren Yizhak, Ami Navon, Polina Stepensky, Nir Hacohen, Tamar Peretz, Andre Veillette, Rotem Karni, Galit Eisenberg, Michal Lotem

Research output: Contribution to journalArticlepeer-review

Abstract

SLAMF6 is a homotypic receptor of the Ig-superfamily associated with progenitor-exhausted T cells. Here we show that in humans, SLAMF6 has three splice isoforms involving its V-domain. Although the canonical receptor inhibited T-cell activation through SAP recruitment, the short isoform SLAMF6D17–65 had a strong agonistic effect. The costimulatory action depended on protein phosphatase SHP1 and led to a cytotoxic molecular profile mediated by the expression of TBX21 and RUNX3. Patients treated with immune checkpoint blockade showed a shift toward SLAMF6D17–65 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6D17–65 expression in human tumor-infiltrating lymphocytes and improved their capacity to inhibit human melanoma in mice. The yin-yang relationship of SLAMF6 splice isoforms may represent a balancing mechanism that could be exploited to improve cancer immunotherapy.

Original languageEnglish
Pages (from-to)637-650
Number of pages14
JournalCancer immunology research
Volume9
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

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