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Session: Session 2

Alternative neo-antigens for breast cancer: study of AltProts and their role in MHC Class I presentation

Eunice CARDOSO MORENO1, Isabelle FOURNIER1, Tristan CARDON1, Michel SALZET1

1INSERM U1192 Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (PRISM), Villeneuve d'ascq, France

Research into neoantigens for the development of cancer immunotherapies faces a major challenge. Since 2011, alternative proteins (AltProts) derived from mRNA regions traditionally described as non-coding, such as the 3' and 5' UTRs, as well as reading frame shifts and various non-coding RNAs (ncRNA, lncRNA, circRNA), have emerged as a potential new source of biomarkers for various cancers, including ovarian, breast and glioblastoma.

AltProts, which are smaller than the reference proteins, could have distinct biological functions and play a crucial role in the immune surveillance of cancers. In our laboratory, previous studies on ovarian cancer have revealed that some of these AltProts, such as HLA-B associated AltProt IP_2292176 and HLA-A associated AltProt IP_2284785, could be involved in antigen presentation via the major histocompatibility complex class I (MHC-I). This suggests that these AltProt could replace β2-microglobulin (B2M), an essential component of MHC-I, or the immunopeptides traditionally presented by MHC-I, there by modulating the immune response against tumour cells.

Our research aims to answer the following question: how do AltProts participate in the presentation of neoantigens by MHC-I? To move towards personalised medicine, we are investigating the identification of new neoantigens specific to the surface of breast cancer cells, enabling them to be distinguished from non-cancerous cells. To do this, we will optimise the co-immunoprecipitation of HLAs with a pan-specific antibody to HLAs (W6/32). We will then use tandem mass spectrometry (LC-MS/MS) to identify potential HLA interactors, with a focus on the possible AltProts involved, in order to understand the mechanisms of the MHC-I presentation. In addition, we will characterise the immunopeptides presented by MHC-I in breast cancer and compare these peptides between healthy and cancer cells to identify differentially expressed neoantigens.