Building matrigenDB- a novel compendium of MHC-I mediated matrisome neoantigens in cancer

The extracellular matrix (ECM) - together with the enzymes, growth factors, and accessory proteins it associates to (~1000 genes) - is known as the matrisome1,2. Dysregulations of the ECM are of the utmost importance for tumour progression and have an impact on tumour cells as well as stromal cells in the tumour microenvironment (TME). The role the matrisome plays in cancer has been long established. In fact, all the “hallmarks of cancer” that fuel cancer growth3,4 are arguably modulated by the biochemical and biomechanical signals from the peri-cancerous ECM5,6. While an increasing body of evidence points to the benefits of co-targeting the matrix in cancer to therapeutic advantage given how the cell-matrix interactions are central to shaping all biological systems7, much less is known about how mutations in the ECM interact with the various immune system mediated mechanisms in play during tumour propagation and growth. Central to our research is the hypothesis that an adaptive immune response can be triggered by Major-Histocompatibility-I (MHC-I) mediated matrisome neoantigens- small immunogenic peptides originating from mutations in matrisome genes accumulated over the course of tumorigenesis and capable of initiating a Cytotoxic T Lymphocyte (CTL) response to help eliminate deleterious cells.

We created a unique bioinformatics workflow harnessing the mutations spanning the entire exome pan-cancer from The Cancer Genome Atlas (TCGA) and using them to derive all possible MHC-I mediated neoantigens, with a particular focus on matrisome neoantigens. The resulting manually curated, wet-lab translatable resource- MatriGenDB, is a first-of-its-kind compendium to exist for the ECM community. Our work points to almost 142278 putative matrisome neoantigens that are potentially immunogenic, of which 77 have been found to be in published works, pointing to a robust tool with universal applicability.