The immunopeptidome from a genomic perspective:Establishing the noncanonical landscape of MHC class I–associated peptides

G.B., D.B., K.W., A.P., R.F., T.R.H., S.K., and J.A.A. received support from Fundacja na rzecz Nauki Polskiej (FNP) (grant ID: MAB/3/2017). D.R.G. received support from Genome Canada & Genome BC (grant ID: 264PRO). D.J.H. received support from NuCana plc (grant ID: SMD0-ZIUN05). H.A. received support from Swedish Cancer Foundation (grant ID: 211709). H.G. received support from United Kingdom Research and Innovation (UKRI) (grant ID: EP/S02431X/1). C.P. received support from Fundação para a Ciência e a Tecnologia (FCT) through LASIGE Research Unit (grant ID: UIDB/00408/2020 and UIDP/00408/2020). A.L. F.M.Z., C.P., A.R., A.P., and J.A.A. received support from European Union’s Horizon 2020 research and innovation programme (grant ID: 101017453). C.B. received support from Agence Nationale de la Recherche (ANR) through GRAL LabEX (grant ID: ANR-10-LABX-49-01) and CBH-EUR-GS 32 (grant ID: ANR-17-EURE0003). S.N.S. received support from Cancer Research UK (CRUK) and the Chief Scientist's Office of Scotland (CSO): Experimental Cancer Medicine Centre (ECMC) (grant ID: ECMCQQR-2022/100017). A.L. received support from Chief Scientist's Office of Scotland (CSO) NRS Career Researcher Fellowship. R.O.N. received support from CRUK Cambridge Centre Thoracic Cancer Programme (grant ID: CTRQQR-2021\100012).Tumor antigens can emerge through multiple mechanisms, including translation of non-coding genomic regions. This non-canonical category of antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry to enable the discovery of non-canonical MHC-associated peptides (ncMAPs) from non-coding regions. Considering that the emergence of tumor antigens can also involve post-translational modifications, we included an open search component in our pipeline. Leveraging the wealth of mass spectrometry-based immunopeptidomics, we analyzed 26 MHC class I immunopeptidomic studies of 9 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant post-translational modifications, using spectral matching and controlled their false discovery rate (FDR) to 1%. Interestingly, the non-canonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 54.85%. Here, we reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targeting agents for T-cell therapies or vaccine development.Publisher PDFPeer reviewe

A Comprehensive Review of Neurodegenerative Manifestations of SARS-CoV-2

The World Health Organization reports that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted a staggering 770 million individuals to date. Despite the widespread nature of this viral infection, its precise effects remain largely elusive. This scientific inquiry aims to shed light on the intricate interplay between SARS-CoV-2 infection and the development of neurodegenerative disorders—an affliction that weighs heavily on millions worldwide and stands as the fourth most prevalent cause of mortality. By comprehensively understanding the repercussions of SARS-CoV-2 on neurodegenerative disorders, we strive to unravel critical insights that can potentially shape our approach to the diagnosis, prevention, and treatment of these debilitating conditions. To achieve this goal, we conducted a comprehensive literature review of the scientific data available to date showing that SARS-CoV-2 infection is associated with increased risk and severity of neurodegenerative disorders, as well as altered expression of key genes and pathways involved in their pathogenesis