Characterization of the ribosome generating peptides for major histocompatibility class I (MHC-1) tolerance from pre-spliced mRNAs.

Cancer vaccines, CAR T cells and immune checkpoint inhibitors exemplify how the immune system can be exploited for cancer treatments.

A cornerstone in the efficacy of these therapeutic approaches is the presentation of neoantigens on major histocompatibility (MHC) class I molecules.

There are three outstanding questions to better predict the efficacy and potential resistance of these therapeutic approaches. 1) Do all tumour cells present the same neoantigens, 2) do tumour cells change the expression of neoantigens and 3) can the expression of neoantigens be manipulated? To address these Qs, we focus on the regulation of neoantigen synthesis.

The proposal is based on previous works and new strong preliminary data showing that the translation of pre-spliced mRNAs generates MHC class I peptide substrates for immune tolerance.

Our aims are: i) characterize this event and how it is regulated ii) identify the composition of the non-canonical translating ribosome, iii) determine its subcellular localisation and iv) manipulate the synthesis of neoantigens.Outcome:-basic insights on a novel mRNA translation event-how neoantigens/MHC-1 peptides are synthesised.

The impact:-basic new cell biology and how the immune tolerates alternative tissue specific splice products-manipulating neoantigens expression  -understanding CD8 T cell-based immune therapies and resistance development-improve mRNA cancer vaccines Wider implications:-the origin of neoantigens in viral & autoimmune disease.