Mismatch Repair Deficient Neoantigen and Associated Circulating T-Cell Receptor Repertoires in Lynch Syndrome

Advisor: Eduardo Vilar-Sanchez, MD, PhD

Lynch Syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome and constitutes the perfect model to understand DNA mismatch repair deficient (MMRd) carcinogenesis. LS patients develop MMRd tumors with high loads of shared neoantigens (neoAgs), which are recognized by the immune system. Previous research has focused on discovering neoAgs and their potential as vaccine targets in LS patients. However, these studies have identified shared neoAgs from cancers, lacking detailed information on targetable neoAgs from precancerous lesions. Understanding this pre-cancer derived neoAg landscape is crucial for effective cancer interception. Furthermore, the T-cell receptor (TCR) landscape of LS patients has never been assessed. Thus, there is a need for exploring immune-based preventive strategies and gaining insights into the patterns of these recurrent neoAgs and their specific TCRs.

Our neoAg study consisted of whole exome sequencing and mRNA sequencing on 69 colorectal lesions, that included 12 cancers, 8 advanced pre-cancers, 41 pre-cancers and 8 polyps without malignant potential (PWOMPs). Using this data, an in silico pipeline was developed, which predicted, ranked, and identified the top 100 most recurrent and immunogenic neoAgs that were then validated in vitro using immunological assays. Our results showed that 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were detected in 92% of cancers, 50% of advanced pre-cancers, and 29% of pre-cancers, while no neoAgs were detected in PWOMPs.

For the TCR assessment, I performed TCR-sequencing of 277 PBMCs/blood samples from 102 LS survivors with history of MMRd cancers, 130 LS previvors, with no history of MMRd cancers and 45 controls. My results revelaed that largely expanded MMRd CRC-specific public TCRβs are detectable in the peripheral blood of LS cancer survivors, while LS previvors and controls exhibited MMRd CRC-specific public TCRβs with medium and minimal expansion, respectively. Importantly, we developed a classification model capable of distinguishing LS individuals from controls with excellent performance, based on the presence of a Lynch-associated TCR signature. Among these Lynch-associated TCRβs, several were confirmed to be specific towards CRC and a neoAg originating within these lesions. Finally, we identified a set of TCRβs with some ability to discriminate LS survivors from previvors.

In summary, this study is the first to describe neoAg generation in pre-cancers as well as the circulating TCR repertoires of LS patients. Our results move the field closer towards the development of a universal LS cancer-vaccine and the identification of TCR clones in the peripheral blood of LS carriers that could serve as biomarkers of cancer.

Advisory Committee:
Eduardo Vilar-Sanchez, MD, PhD, Chair
E.Scott Kopetz, MD, PhD
Gregory Lizee, PhD
Alexandre Reuben, PhD
Paul Scheet, PhD
Linghua Wang, PhD

Attend via Zoom
Meeting ID: 871 9790 7447
Password: 514528