Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors
BackgroundMicrosatellite 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.MethodsIncluding 1,236 CRC tumors...
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Frontiers Media S.A.
2024-12-01
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| author | Claire E. Thomas Yasutoshi Takashima Evertine Wesselink Tomotaka Ugai Tomotaka Ugai Tomotaka Ugai Robert S. Steinfelder Daniel D. Buchanan Daniel D. Buchanan Daniel D. Buchanan Conghui Qu Li Hsu Li Hsu Andressa Dias Costa Steven Gallinger Robert C. Grant Jeroen R. Huyghe Sushma S. Thomas Shuji Ogino Shuji Ogino Shuji Ogino Shuji Ogino Amanda I. Phipps Amanda I. Phipps Jonathan A. Nowak Jonathan A. Nowak Ulrike Peters Ulrike Peters |
| author_facet | Claire E. Thomas Yasutoshi Takashima Evertine Wesselink Tomotaka Ugai Tomotaka Ugai Tomotaka Ugai Robert S. Steinfelder Daniel D. Buchanan Daniel D. Buchanan Daniel D. Buchanan Conghui Qu Li Hsu Li Hsu Andressa Dias Costa Steven Gallinger Robert C. Grant Jeroen R. Huyghe Sushma S. Thomas Shuji Ogino Shuji Ogino Shuji Ogino Shuji Ogino Amanda I. Phipps Amanda I. Phipps Jonathan A. Nowak Jonathan A. Nowak Ulrike Peters Ulrike Peters |
| author_sort | Claire E. Thomas |
| collection | DOAJ |
| description | BackgroundMicrosatellite 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.MethodsIncluding 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.ResultsCompared 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)].DiscussionMSI-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.SignificanceThis 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. |
| format | Article |
| id | doaj-art-3bffcf3da7284571b34a3d5bc4fca672 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-3bffcf3da7284571b34a3d5bc4fca6722025-08-20T02:40:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-12-011510.3389/fimmu.2024.15058961505896Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumorsClaire E. Thomas0Yasutoshi Takashima1Evertine Wesselink2Tomotaka Ugai3Tomotaka Ugai4Tomotaka Ugai5Robert S. Steinfelder6Daniel D. Buchanan7Daniel D. Buchanan8Daniel D. Buchanan9Conghui Qu10Li Hsu11Li Hsu12Andressa Dias Costa13Steven Gallinger14Robert C. Grant15Jeroen R. Huyghe16Sushma S. Thomas17Shuji Ogino18Shuji Ogino19Shuji Ogino20Shuji Ogino21Amanda I. Phipps22Amanda I. Phipps23Jonathan A. Nowak24Jonathan A. Nowak25Ulrike Peters26Ulrike Peters27Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United StatesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United StatesDivision of Human Nutrition and Health, Wageningen University & Research, Wageningen, NetherlandsProgram in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United StatesCancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston, MA, United StatesPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United StatesColorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, AustraliaUniversity of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, VIC, AustraliaGenomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, AustraliaPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United StatesPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States0Department of Biostatistics, University of Washington, Seattle, WA, United States1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada3Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United StatesPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United StatesProgram in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States4Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States5Institute of Science Tokyo, Tokyo, JapanPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States6Department of Epidemiology, University of Washington, Seattle, WA, United StatesProgram in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States7Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, United StatesPublic Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States6Department of Epidemiology, University of Washington, Seattle, WA, United StatesBackgroundMicrosatellite 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.MethodsIncluding 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.ResultsCompared 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)].DiscussionMSI-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.SignificanceThis 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1505896/fullmicrosatellite instabilityhypermutationDNA mismatch repairT cellsepithelialstromal |
| spellingShingle | Claire E. Thomas Yasutoshi Takashima Evertine Wesselink Tomotaka Ugai Tomotaka Ugai Tomotaka Ugai Robert S. Steinfelder Daniel D. Buchanan Daniel D. Buchanan Daniel D. Buchanan Conghui Qu Li Hsu Li Hsu Andressa Dias Costa Steven Gallinger Robert C. Grant Jeroen R. Huyghe Sushma S. Thomas Shuji Ogino Shuji Ogino Shuji Ogino Shuji Ogino Amanda I. Phipps Amanda I. Phipps Jonathan A. Nowak Jonathan A. Nowak Ulrike Peters Ulrike Peters Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors Frontiers in Immunology microsatellite instability hypermutation DNA mismatch repair T cells epithelial stromal |
| title | Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors |
| title_full | Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors |
| title_fullStr | Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors |
| title_full_unstemmed | Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors |
| title_short | Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors |
| title_sort | association between somatic microsatellite instability hypermutation status and specific t cell subsets in colorectal cancer tumors |
| topic | microsatellite instability hypermutation DNA mismatch repair T cells epithelial stromal |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1505896/full |
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