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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1505896

Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors

Provisionally accepted
Claire E Thomas Claire E Thomas 1*Yasutoshi Takashima Yasutoshi Takashima 2Vera Wesselink Vera Wesselink 3Tomotaka Ugai Tomotaka Ugai 4Robert S Steinfelder Robert S Steinfelder 1Daniel Buchanan Daniel Buchanan 5Conghui Qu Conghui Qu 1Li Hsu Li Hsu 1Andressa Dias Costa Andressa Dias Costa 2Steven Gallinger Steven Gallinger 1,6Robert C Grant Robert C Grant 7Jeroen Huyghe Jeroen Huyghe 1Sushma S Thomas Sushma S Thomas 1Shuji Ogino Shuji Ogino 4Amanda I Phipps Amanda I Phipps 1Jonathan A Nowak Jonathan A Nowak 2Ulrike Peters Ulrike Peters 1
  • 1 Fred Hutchinson Cancer Center, Seattle, United States
  • 2 Dana–Farber Cancer Institute, Boston, Massachusetts, United States
  • 3 Wageningen University and Research, Wageningen, Netherlands
  • 4 Harvard Medical School, Boston, Massachusetts, United States
  • 5 The University of Melbourne, Parkville, Victoria, Australia
  • 6 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
  • 7 Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada

The final, formatted version of the article will be published soon.

    Background: Microsatellite instability-high (MSI-high) tumors comprise ~15% of sporadic colorectal cancers (CRC) and are associated with elevated T cell infiltration. However, the universality of this response across T cell subtypes with distinct functions is unknown. Methods: Including 1,236 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and DAPI) multispectral immunofluorescence assay. MSI status was assessed through polymerase chain reaction or immunohistochemical assays. We used multivariable ordinal logistic regression to estimate odds ratios (OR per increasing quantile) and 95% confidence intervals (CIs) for the association of MSI status with quantiles of T cell densities in either tumor epithelial or stromal tissue areas. Results: Compared to microsatellite instability low or microsatellite stable (MSI-low/MSS) tumors, MSI-high status was associated with higher density for the majority of immune subsets (twelve out of eighteen) in both epithelial and stromal tissue areas. The strongest associations were for CD3+CD8+ T cells in epithelial areas [OR (95% CI) for naive, memory, and regulatory subsets = 3.49 (2.57, 4.75); 2.82 (2.10, 3.78); 3.04 (2.24, 4.13), respectively]. Conversely, stromal area CD3+CD4+ memory T cells were inversely associated [OR (95% CI) = 0.68 (0.51, 0.91)]. Discussion: MSI-high status was strongly associated with higher densities of most T cell subsets in both epithelial and stromal tissue areas. Our investigation supports efforts to identify patients who may be more likely to respond to current immunotherapy treatments. Significance: This study helps us better understand how a clinically relevant tumor phenotype, microsatellite instability status, is related to different functioning T cell densities in colorectal tumors, which may impact future immunotherapy strategies.

    Keywords: Microsatellite Instability, hypermutation, DNA Mismatch Repair, T cells, Epithelial, stromal, colorectal cancer, somatic

    Received: 03 Oct 2024; Accepted: 03 Dec 2024.

    Copyright: © 2024 Thomas, Takashima, Wesselink, Ugai, Steinfelder, Buchanan, Qu, Hsu, Dias Costa, Gallinger, Grant, Huyghe, Thomas, Ogino, Phipps, Nowak and Peters. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Claire E Thomas, Fred Hutchinson Cancer Center, Seattle, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.