Alternative splicing of modulatory immune receptors: a targetable mechanism for anti-cancer immunotherapy
2Hadassah Cancer Research Institute, Hadassah medical Organization, Israel
3Biochemistry and Molecular Biology, Faculty of Medicine Hebrew University, Israel
4The Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine Hebrew University, Israel
Alternative splicing (AS) is the production of variant transcripts which differ from the constitutive gene and produce proteins with diverse functions. It is clear that the isoform ratio varies from tissue to tissue and from cell state to state. The immune system is no exception to this rule, and T cell activation is associated with a dynamic expression as well as a shifted ratio of RNA transcripts and their isoforms.
In this talk we will shed light on typical patterns of AS in immune receptors of the Ig and TNFR super-families. The coding of agonistic and antagonistic sequences in one gene will be demonstrated in prominent check-point receptors such as PD-1.
A genome-wide screen was developed to register splicing events of potential significance and to evaluate their functional implications. A multi-guide arrayed screen was carried out using the CRISPR-Cas 9 system to evaluate the impact of AS on cytokine secretion, the strength of the immune synapse and the interaction with monocyte-derived APCs.
Lastly, single splicing events will be evaluated to verify the applicability of the system to the development of new immunotherapeutic targets.