Early cancer detection and prophylactic intervention remain the primary strategies for reducing colorectal carcinoma incidence and mortality. Although the immune microenvironment and tumor-associated antigens have been shown to play a pivotal role in carcinogenesis, the factors shaping immune dynamics during the premalignant phase remain poorly understood. In this study, we performed a comprehensive multimodal characterization of the immune microenvironment in 258 longitudinal premalignant colorectal lesions. Using a discovery cohort of 135 lesions from 26 patients stratified by low versus high polyp development rate, we identified distinct immune states associated with polyp burden. These findings were validated in an independent cohort of 123 lesions from 43 patients. Lesions from patients with low polyp development rates exhibited signatures of robust immune surveillance characterized by enhanced adaptive immune infiltration, including defined T cell subsets, and a higher prevalence of mature tertiary lymphoid structures compared with lesions from patients with high polyp frequency. These immune features were accompanied by increased expression of noncoding RNAs. These transcripts were predicted to encode noncanonical antigens with high MHC-I (major histocompatibility complex class I) binding affinity, potentially increasing lesion immunogenicity. We propose that early carcinogenesis is shaped by the immune microenvironment in association with noncoding RNAs, revealing potential early biomarkers in individuals at high risk of developing colorectal cancer.
Morgand et al. (Wed,) studied this question.
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