Mass General Brigham study tracks how the tumor microenvironment develops during progression, signaling an opportunity for early detection and risk prediction
Colorectal cancer precursor lesions are benign growths that can develop into colorectal cancer (CRC) over time, through either a conventional or serrated pathway. Understanding how the immune system reacts to these precursor lesions could further the understanding of CRC development as well as potential treatment options. To this end, a new study from researchers at Mass General Brigham explores T cell behavior and distribution in the colorectal area as cancer progresses, detecting distinct patterns associated with progression. Results are published in Cancer Immunology Research.
"Our study revealed differences in the immune microenvironment based on T-cell infiltration patterns leading to the development of CRC," said senior author Shuji Ogino, MD, PhD, MS, American Cancer Society Professor and the Chief of the Molecular Pathological Epidemiology Program in the Mass General Brigham Department of Pathology. "This new knowledge has the potential to help us detect CRC earlier by predicting risk."
The team used tissue from tumors that had occurred over decades in people who were followed as part of three large-scale prospective cohort studies to perform fluorescent assays targeting proteins in the immune system. Using high-tech imaging platforms and machine learning, they were able to analyze 1,825 tissue samples, including 790 precancerous lesions and 1,035 with CRC. With these samples, the researchers identified T cells and categorized them by function, activation status and location.
They found that T-cell infiltration varied significantly across the spectrum from normal tissue to precancerous lesions to cancer. Differences in T cell types and densities indicated which precancerous lesions may be more likely to progress while spatial organization of T cells appeared to influence the effectiveness of the immune response.
"Understanding T cell patterns in precancerous lesions could help us detect CRC earlier, predict risks, and develop therapeutic approaches," said Ogino. "Much beyond that, this study is just the beginning of our prospective cohort incident-tumor biobank method (PCIBM)-based study of long-term, time-varying risk factors and tumor profiling of both colorectal precancers and cancers together. Such a comprehensive longitudinal study has never been conducted in human history. We are making history in this regard."
Authorship: In addition to Ogino, authors include Yasutoshi Takashima, Andressa Dias Costa, Naohiko Akimoto, Tomotaka Ugai, Phoenix Bell, Juha P. Väyrynen, Jason L. Hornick, Mari Mino-Kenudson, Yuxue Zhong, Satoko Ugai, Koichiro Haruki, Qian Yao, Kosuke Matsuda, Mayu Higashioka, Daniel D. Buchanan, Amanda I. Phipps, Ulrike Peters, Marios Giannakis, Mingyang Song, Andrew T. Chan, Charles S. Fuchs, and Jonathan A. Nowak.
Disclosures: Fuchs is currently employed by Genentech, a subsidiary of Roche, and previously served as a consultant for Agios, Bain Capital, Bayer, Celgene, Dicerna, Eli Lilly, Entrinsic Health, Five Prime Therapeutics, Genentech, Gilead Sciences, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. Fuch also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health. Chan previously served as a consultant for Bayer Healthcare and Pfizer. Giannakis receives research funding from Janssen and Sunbird Bio, consulting fees from Nerviano Medical Sciences, and honoraria from OncLive and PER. This study was not funded by any of these companies. Peters was a consultant with AbbVie and her family is holding individual stocks for the following companies: Amazon, Boeing Company, BioNTech, BYD Company Limited, Crowdstrike Holdings Inc, CureVac, Google/Alphabet, Microsoft Corp, MicroStrategy Inc, NVIDIA Corp, Stellantis. No other conflicts of interest exist. The other authors declare that they have no conflicts of interest.
Funding: This work was supported by U.S. National Institutes of Health (NIH) grants (P01 CA87969; UM1 CA186107; P01 CA55075; UM1 CA167552; U01 CA167552; R01 CA151993; R35 CA197735; R21 CA230873; R01 CA248857; R50 CA274122); by Cancer Research UK Grand Challenge Award (C10674/A27140); by the Prevent Cancer Foundation; and by the American Institute for Cancer Research. Chan is an American Cancer Society Clinical Research Professor. Ogino is an American Cancer Society Clinical Research Professor (CRP-24-1185864-01-PROF). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Paper cited: Takashima Y et al. "T Lymphocyte Subset Features and Distributions in the Colorectal Precancer-Cancer Spectrum" Cancer Immunology Research DOI: 10.1158/2326-6066.CIR-25-0481
