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. 2021 Jun;9(6):637-650.
doi: 10.1158/2326-6066.CIR-20-0800. Epub 2021 Mar 24.

Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions

Emma Hajaj  1   2   3 , Elad Zisman  1   2   3 , Shay Tzaban  1   2   3 , Sharon Merims  1   2 , Jonathan Cohen  1   2   3 , Shiri Klein  1   2   3 , Shoshana Frankenburg  1   2 , Moshe Sade-Feldman  4   5   6 , Yuval Tabach  7 , Keren Yizhak  8 , Ami Navon  9 , Polina Stepensky  10 , Nir Hacohen  4   5   6 , Tamar Peretz  1 , André Veillette  11 , Rotem Karni  12 , Galit Eisenberg  1   2   3 , Michal Lotem  13   2   3
Affiliations

Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions

Emma Hajaj et al. Cancer Immunol Res. 2021 Jun.

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 SLAMF6Δ17-65 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 SLAMF6Δ17-65 in peripheral blood T cells. We developed splice-switching antisense oligonucleotides (ASO) designed to target the relevant SLAMF6 splice junction. Our ASOs enhanced SLAMF6Δ17-65 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.

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