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Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

ABSTRACT: Lynch syndrome (LS) patients are at markedly increased risk for colorectal cancer. It is being increasingly recognized that the immune system plays an essential role in LS tumor development. Therefore, immune interception strategies are emerging as a novel way to prevent cancer in LS. This phase Ib, placebo-controlled, randomized clinical trial and a co-clinical trial using a LS mouse model and patient-derived organoids aims to evaluate the safety and tolerability as well as to discover novel molecular pathways involved in the activity of Naproxen as chemoprevention in LS patients.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE144381 | GEO | 2020/06/25

REPOSITORIES: GEO

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Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

Project description:Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

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Project description:Lynch syndrome (LS) patients develop DNA mismatch repair deficient tumors which generate high loads of neoantigens (neoAgs), thus constituting a well-defined population that can benefit from cancer immune-interception strategies, including neoantigen-based vaccines. Using paired whole-exome sequencing and mRNAseq of colorectal cancers (CRC) (n=13) and pre-cancers (n=61) from our LS patient cohort (N=46), we performed in-silico prediction and immunogenicity ranking of highly recurrent frameshift-neoags, followed by their in-vitro validation. We described the somatic mutation landscape in all cancers and pre-cancers, and showed that mutation burden is positively correlated with neoAgs load. Furthermore, our in-vitro validation showed a 65% validation rate of our top 100 predicted neoags. Consistent with neoAgs burden, our transcriptomic results revealed increased infiltration of CD8+ and CD4+ T-cells in microsatellite unstable samples. Overall, our neoAgs catalog and all other findings, improve our understanding of cancer development in LS and guide us towards the advancement of immunoprevention vaccine strategies.

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