Modifying the splicing of the immune receptor SLAMF6 is a potentially new melanoma immunotherapy
2Medical School, Hebrew University , Jerusalem, Israel
SLAMF6 is a homotypic receptor abundantly expressed on CD8+ T-lymphocytes and thus of interest for its role in anti-tumor response. We evaluated two isoforms of the SLAMF6 gene: The `canonical` sequence, and SLAMF6Δ17-65 missing part of exon-2. Using existing databases and our-own human-derived T-cell samples, we showed that both isoforms are constitutively apparent on T-cells.
Melanoma cells aberrantly expressing canonical SALMF6 had distinct inhibitory effect on cognate TILs (Tumor infiltrating lymphocytes). However, to our surprise the opposite was observed with SLAMF6Δ17-65. Melanoma expressing this isoform enhanced IFN-γ production by cognate TILs significantly and reproducibly.
In line with this, the exclusive expression of the short isoform in Jurkat cells was associated with a three-fold increase in IL-2 secretion. Therefore, we showed that SLAMF6Δ17-65 isoform has a strong agonistic effect on T cell activation while its canonical isoform is an inhibitor.
Using antisense oligonucleotide (ASO) designed to target SLAMF6 splice junction, we managed to shift the splicing in Jurkat cells, increasing the short isoform on the account of the canonical isoform. As an outcome, cells expressing higher levels of SLAMF6Δ17-65 had a significantly improved function.
In melanoma patients receiving PD-1 inhibitory antibody, a transition was noted in SLAMF6 isoforms ratio in peripheral blood T-cells, favoring a rise in the shorter isoform, which was most emphasized in patients with auto-immune side-effects (n=7), this may suggest a biological-relevant new regulatory mechanism that T-cells adopt along their activation. The agonistic effect achieved by splice diverting ASO may be exploited in the future for cancer immunotherapy.