Title: Peptide editing in the MHC I antigen processing pathway and its relevance to cancer
Funder: Cancer Research UK

Abstract: • Background Antigen processing and presentation is the key pathway underpinning the natural or artificial induction of anti-tumour cytotoxic T lymphocytes (CTL) because it generates the ligands that activate them. These are short tumour-derived peptides presented by polymorphic MHC class I molecules. They are selected by a process of peptide editing involving several intracellular cofactors, some of which are themselves polymorphic. We have captured these features in computational models which can be used as tools to investigate how peptide editing influences the repertoire of tumour derived peptides that are displayed by MHC I and how they dictate the specificity of CD8+ T cell responses to tumours. • Aims Aim 1: To establish the mechanism of MHC I allomorph-sensitive, cofactor assisted peptide optimisation and to establish the impact of polymorphism on ERAP1-mediated peptide trimming. Aim2: To incorporate Tapasin, TAPBPR and ERAP 1 molecular mechanism into a systems-level understanding of peptide editing using computational models as a tool. • Methods Aim 1: We will combine computational modelling with biophysical techniques, including hydrogen deuterium exchange mass spectrometry to study protein dynamics, and a range of in vitro and in cellulo assays to relate structural information to the peptide editing function of tapasin and TAPBPR and to peptide trimming by ERAP1. Aim2: We will incorporate new molecular mechanism into computational models and optimise them to predict the cell surface abundance of very large numbers of peptides. We will analyse immunopeptidomes from cell lines and human tumour samples to validate the models and deliver deeper understanding of how MHC I and ERAP1 polymorphism combine with tapasin and TAPBPR function to control global peptide presentation in cancer. • How the results of this research will be used Mechanism based modelling offers a way of using very detailed, yet functionally crucial information to predict antigen presentation in complex systems, such as the tumour microenvironment, and will guide the choice of epitopes to use in anti-cancer vaccines. This will include epitopes that are resistant to changes in tapasin, TAPBPR and ERAP1 expression as a result of tumour evolution. Also, polymorphic variation of ERAP1 and Tapasin may be good biomarkers of incidence and prognosis for some cancers and predict responses to vaccines, or response to checkpoint blockade immunotherapy: allowing a more targeted approach to conventional therapies and to new vaccination based therapy.

Lay abstract: • Background Antigen processing and presentation is the key pathway underpinning the natural or artificial induction of anti-tumour cytotoxic T lymphocytes (CTL) because it generates the ligands that activate them. These are short tumour-derived peptides presented by polymorphic MHC class I molecules. They are selected by a process of peptide editing involving several intracellular cofactors, some of which are themselves polymorphic. We have captured these features in computational models which can be used as tools to investigate how peptide editing influences the repertoire of tumour derived peptides that are displayed by MHC I and how they dictate the specificity of CD8+ T cell responses to tumours. • Aims Aim 1: To establish the mechanism of MHC I allomorph-sensitive, cofactor assisted peptide optimisation and to establish the impact of polymorphism on ERAP1-mediated peptide trimming. Aim2: To incorporate Tapasin, TAPBPR and ERAP 1 molecular mechanism into a systems-level understanding of peptide editing using computational models as a tool. • Methods Aim 1: We will combine computational modelling with biophysical techniques, including hydrogen deuterium exchange mass spectrometry to study protein dynamics, and a range of in vitro and in cellulo assays to relate structural information to the peptide editing function of tapasin and TAPBPR and to peptide trimming by ERAP1. Aim2: We will incorporate new molecular mechanism into computational models and optimise them to predict the cell surface abundance of very large numbers of peptides. We will analyse immunopeptidomes from cell lines and human tumour samples to validate the models and deliver deeper understanding of how MHC I and ERAP1 polymorphism combine with tapasin and TAPBPR function to control global peptide presentation in cancer. • How the results of this research will be used Mechanism based modelling offers a way of using very detailed, yet functionally crucial information to predict antigen presentation in complex systems, such as the tumour microenvironment, and will guide the choice of epitopes to use in anti-cancer vaccines. This will include epitopes that are resistant to changes in tapasin, TAPBPR and ERAP1 expression as a result of tumour evolution. Also, polymorphic variation of ERAP1 and Tapasin may be good biomarkers of incidence and prognosis for some cancers and predict responses to vaccines, or response to checkpoint blockade immunotherapy: allowing a more targeted approach to conventional therapies and to new vaccination based therapy.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS