Untangling the mechanisms behind SLAMF6 switchy nature

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Invited_Lecture

Check Point Pathways, Cancer and Immunotherapy from Experimental Models to Treatment

Deciphering SLAMF6’s uncanny mechanism of switch

Michal Lotem

Historically, SLAM family receptors were studied for their part in X-linked lymphoproliferative disease (XLP), a complex genetic immune dysfunction due to a mutation of their adaptor, SAP. For years, it was unclear if loss of SAP converts all SFRs into “super-inhibitory” receptors or the contrary- unleash lymphocyte to proliferate and resist apoptosis. The role of SLAMF6, common to T cells, was held a dual functioning receptor consequent to the interplay between SAP and SHP-1 and 2, protein phosphatases that bind to tyrosines on the cytoplasmic tail of the receptor.

With a new Pmel-1 x SLAMF6 KO mice we found that in its full-length form, SLAMF6 is a strongly negative determinant of tumor immunity. In this talk a form of SLAMF6 will be described, that generates a strong agonistic signal in CD8 T cells, which is opposite to the effect of the parental receptor. Therapeutic models targeting SLAMF6 will be discussed and splicing modulation via regulatory elements will be described as a potential new avenue to modify T cells.