Colorectal carcinomas in Lynch syndrome (LS) patients arise in a background of mismatch repair deficiency that leads to the accumulation of high numbers of mutations and neoantigens, thus causing infiltration by abundant tumor-infiltrating lymphocytes, a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a knowledge gap with regards to the level of immune activation and the assessment of mutation and neoantigen rates in LS premalignancy. We performed whole transcriptomic analysis using next-generation sequencing in a total of 28 colorectal polyps (26 tubular adenomas and 2 hyperplastic polyps) from 21 patients diagnosed with LS (n=11) and FAP (n=10) as comparators and a model of mismatch repair proficient colorectal premalignancy.Overall, LS polyps presented with low mutational and neoantigen rates but displayed a strinking immune activation profile characterized by CD4 T-cells, proinflammatory (TNF, IL12) and checkpoint molecules (LAG-3 and PD-L1). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were secondary to accumulation of indels enriched for deregulation of DNA damage repair pathways (ATM and BRCA1 signaling). Our findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in Lynch syndrome.

Citation Format: Kyle Chang. Lynch syndrome premalignancy upregulates immune checkpoints independently from neoantigen and mutational rates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1256.