To characterize the immune profile of premalignant lesions, or polyps, in patients with the mismatch repair (MMR)-associated disease, Lynch Syndrome (LS), Chang et al. performed RNA sequencing on polyps from patients with LS and the non-MMR disease, familial adenomatous polyposis. Their analysis revealed an immune activated profile (CD4+ T cell infiltration, proinflammatory molecules, and checkpoint molecules) in LS premalignant polyps that was independent of mutational rates, neoantigen formation, or mismatch repair status, challenging the current paradigm.
Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS. Design, Setting, and Participants: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. Main Outcomes and Measures: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. Results: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). 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 comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling). Conclusions and Relevance: These 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 LS.
Author Info: (1) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer
Author Info: (1) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. (2) Department of Pathology, University of Texas MD Anderson Cancer Center, Houston. (3) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (4) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (5) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (6) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (7) Nouscom SRL, Rome, Italy. (8) Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston. (9) Nouscom SRL, Rome, Italy. (10) ReiThera SRL, Rome, Italy. (11) Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy. (12) Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. (13) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (14) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston. (15) Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston. (16) Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. (17) Nouscom SRL, Rome, Italy. CEINGE, Naples, Italy. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. (18) Nouscom SRL, Rome, Italy. (19) Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston. (20) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. (21) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.
