Grant Number:	5R01CA248857-06 Interpret this number
Primary Investigator:	Peters, Ulrike
Organization:	Fred Hutchinson Cancer Center
Project Title:	Interdisciplinary Epidemiologic Consortium to Investigate T-Cell Response in Colorectal Cancer
Fiscal Year:	2024

PROJECT SUMMARY / ABSTRACT The immune system has pivotal influence in the evolution and progression of many tumor types, including colorectal cancer (CRC). In particular, the presence of a strong T cell response in CRC, indicating activation of the adaptive immune system, has been associated with better patient outcomes. As such, recently developed immunotherapeutic approaches often attempt to harness the adaptive immune response. Immune cells are an integral component of the tumor microenvironment, and dynamically interact with neoplastic cells. However, our understanding as to the complexity of the T cell response and the factors that drive this response remains limited. The objective of this proposal is to identify genetic, lifestyle, and tumor factors associated with the T cell response in CRC, and to characterize the survival implications of that response. Specifically, in Aim 1 we will examine the relationship of personal characteristics with T cell response in CRC, including the role of (1a) germline genetic variation within human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) genes, and (1b) lifestyle factors (e.g., aspirin use, smoking, alcohol consumption). In Aim 2 we will focus on several colorectal tumor characteristics as they relate to T cell response, including (2a) the presence of Fusobacterium nucleatum and bacterial toxin genes in CRC, and (2b) somatic mutations in key signaling pathways (e.g., WNT signaling and RAS/RAF). In Aim 3, we will evaluate the associations of different aspects of T cell response with CRC survival, accounting for known prognostic factors and the relationships identified in Aims 1-2. To achieve these Aims, we propose to assess the density and spatial distribution of specific T cell subsets using multiplexed immunofluorescence (mIF) to quantify expression levels and co-expression patterns of CD3, CD4, CD8, CD45RO, and FOXP3 at the single cell level. This multiplexed assessment will allow us to examine the epidemiologic and prognostic relevance of numerous metrics of T cell response in CRC. This research will leverage the resources of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). GECCO-CCFR is a large collaborative effort between observational studies of CRC. We have completed genome-wide germline genotyping and have harmonized epidemiologic data regarding a variety of lifestyle factors and personal characteristics for all participating studies. We are conducting DNA sequencing with a panel of 205 human genes and a small number of bacterial genes in CRC tumor tissue. Prospective follow-up for survival is ongoing, and we have harmonized existing survival data. Through this project, we will add information on T cell response in CRC for >2,500 CRC cases to the GECCO-CCFR resource. This project provides an unprecedented opportunity to investigate the epidemiology of the T cell response in CRC and the relationship of that response with personal and tumor characteristics. Insights gained through this novel study could ultimately inform the development and targeted implementation of emerging immunotherapeutic and immunopreventative strategies.




Risk of colorectal cancer and adenoma after an appendectomy: results from three large prospective cohort studies and meta-analysis.
Authors: Zhang Y. , Khil J. , Feng X. , Ugai T. , Ogino S. , Giovannucci E. .
Source: Cancer Causes & Control : Ccc, 2024-07-27 00:00:00.0; , .
EPub date: 2024-07-27 00:00:00.0.
PMID: 39066935
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Machine learning links T-cell function and spatial localization to neoadjuvant immunotherapy and clinical outcome in pancreatic cancer.
Authors: Blise K.E. , Sivagnanam S. , Betts C.B. , Betre K. , Kirchberger N. , Tate B.J. , Furth E.E. , Dias Costa A. , Nowak J.A. , Wolpin B.M. , et al. .
Source: Cancer Immunology Research, 2024-02-21 00:00:00.0; , .
EPub date: 2024-02-21 00:00:00.0.
PMID: 38381401
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Machine learning links T cell function and spatial localization to neoadjuvant immunotherapy and clinical outcome in pancreatic cancer.
Authors: Blise K.E. , Sivagnanam S. , Betts C.B. , Betre K. , Kirchberger N. , Tate B. , Furth E.E. , Dias Costa A. , Nowak J.A. , Wolpin B.M. , et al. .
Source: Biorxiv : The Preprint Server For Biology, 2023-10-23 00:00:00.0; , .
EPub date: 2023-10-23 00:00:00.0.
PMID: 37961410
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Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes.
Authors: Mahmood K. , Thomas M. , Qu C. , Gecco-Ccfr Consortium , Hsu L. , Buchanan D.D. , Peters U. .
Source: Gastroenterology, 2023 Oct; 165(4), p. 1070-1076.e3.
EPub date: 2023-07-14 00:00:00.0.
PMID: 37453563
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Histopathology images predict multi-omics aberrations and prognoses in colorectal cancer patients.
Authors: Tsai P.C. , Lee T.H. , Kuo K.C. , Su F.Y. , Lee T.M. , Marostica E. , Ugai T. , Zhao M. , Lau M.C. , Väyrynen J.P. , et al. .
Source: Nature Communications, 2023-04-13 00:00:00.0; 14(1), p. 2102.
EPub date: 2023-04-13 00:00:00.0.
PMID: 37055393
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Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.
Authors: Williams H.L. , Dias Costa A. , Zhang J. , Raghavan S. , Winter P.S. , Kapner K.S. , Ginebaugh S.P. , Väyrynen S.A. , Väyrynen J.P. , Yuan C. , et al. .
Source: Cancer Research, 2023-02-03 00:00:00.0; 83(3), p. 441-455.
PMID: 36459568
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Prognostic role of detailed colorectal location and tumor molecular features: analyses of 13,101 colorectal cancer patients including 2994 early-onset cases.
Authors: Ugai T. , Akimoto N. , Haruki K. , Harrison T.A. , Cao Y. , Qu C. , Chan A.T. , Campbell P.T. , Berndt S.I. , Buchanan D.D. , et al. .
Source: Journal Of Gastroenterology, 2023-01-17 00:00:00.0; , .
EPub date: 2023-01-17 00:00:00.0.
PMID: 36648535
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Molecular Characteristics of Early-onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison to Later-onset Cases: Molecular Characteristics and Early-onset Colorectal Tumor Subsites.
Authors: Ugai T. , Haruki K. , Harrison T.A. , Cao Y. , Qu C. , Chan A.T. , Campbell P.T. , Akimoto N. , Berndt S. , Brenner H. , et al. .
Source: The American Journal Of Gastroenterology, 2022-12-30 00:00:00.0; , .
EPub date: 2022-12-30 00:00:00.0.
PMID: 36707929
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Authors: Carreras-Torres R. , Kim A.E. , Lin Y. , Díez-Obrero V. , Bien S.A. , Qu C. , Wang J. , Dimou N. , Aglago E.K. , Albanes D. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2022-12-28 00:00:00.0; , .
EPub date: 2022-12-28 00:00:00.0.
PMID: 36576985
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Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer.
Authors: Dias Costa A. , Väyrynen S.A. , Chawla A. , Zhang J. , Väyrynen J.P. , Lau M.C. , Williams H.L. , Yuan C. , Morales-Oyarvide V. , Elganainy D. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2022-12-01 00:00:00.0; 28(23), p. 5167-5179.
PMID: 36129461
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T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients.
Authors: Yin H. , Harrison T.A. , Thomas S.S. , Sather C.L. , Koehne A.L. , Malen R.C. , Reedy A.M. , Wurscher M.A. , Hsu L. , Phipps A.I. , et al. .
Source: Cancer Medicine, 2022-11-07 00:00:00.0; , .
EPub date: 2022-11-07 00:00:00.0.
PMID: 36341526
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Is early-onset cancer an emerging global epidemic? Current evidence and future implications.
Authors: Ugai T. , Sasamoto N. , Lee H.Y. , Ando M. , Song M. , Tamimi R.M. , Kawachi I. , Campbell P.T. , Giovannucci E.L. , Weiderpass E. , et al. .
Source: Nature Reviews. Clinical Oncology, 2022-09-06 00:00:00.0; , .
EPub date: 2022-09-06 00:00:00.0.
PMID: 36068272
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Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science.
Authors: Inamura K. , Hamada T. , Bullman S. , Ugai T. , Yachida S. , Ogino S. .
Source: Gut, 2022-07-12 00:00:00.0; , .
EPub date: 2022-07-12 00:00:00.0.
PMID: 35820782
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Utility of Continuous Disease Subtyping Systems for Improved Evaluation of Etiologic Heterogeneity.
Authors: Li R. , Ugai T. , Xu L. , Zucker D. , Ogino S. , Wang M. .
Source: Cancers, 2022-04-02 00:00:00.0; 14(7), .
EPub date: 2022-04-02 00:00:00.0.
PMID: 35406583
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Authors: Ugai T. , Väyrynen J.P. , Haruki K. , Akimoto N. , Lau M.C. , Zhong R. , Kishikawa J. , Väyrynen S.A. , Zhao M. , Fujiyoshi K. , et al. .
Source: Journal Of The National Cancer Institute, 2022-01-11 00:00:00.0; 114(1), p. 68-77.
PMID: 34264325
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Coffee Intake of Colorectal Cancer Patients and Prognosis According to Histopathologic Lymphocytic Reaction and T-Cell Infiltrates.
Authors: Ugai T. , Haruki K. , Väyrynen J.P. , Borowsky J. , Fujiyoshi K. , Lau M.C. , Akimoto N. , Zhong R. , Kishikawa J. , Arima K. , et al. .
Source: Mayo Clinic Proceedings, 2022 01; 97(1), p. 124-133.
PMID: 34996545
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Authors: Akimoto N. , Väyrynen J.P. , Zhao M. , Ugai T. , Fujiyoshi K. , Borowsky J. , Zhong R. , Haruki K. , Arima K. , Lau M.C. , et al. .
Source: Frontiers In Immunology, 2022; 13, p. 840198.
EPub date: 2022-03-22 00:00:00.0.
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Authors: Väyrynen J.P. , Haruki K. , Lau M.C. , Väyrynen S.A. , Ugai T. , Akimoto N. , Zhong R. , Zhao M. , Dias Costa A. , Borowsky J. , et al. .
Source: Cancer Immunology Research, 2021-12-22 00:00:00.0; , .
EPub date: 2021-12-22 00:00:00.0.
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Authors: Cleary J.M. , Wolpin B.M. , Dougan S.K. , Raghavan S. , Singh H. , Huffman B. , Sethi N.S. , Nowak J.A. , Shapiro G.I. , Aguirre A.J. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2021-12-15 00:00:00.0; 27(24), p. 6622-6637.
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Authors: Borozan I. , Zaidi S.H. , Harrison T.A. , Phipps A.I. , Zheng J. , Lee S. , Trinh Q.M. , Steinfelder R.S. , Adams J. , Banbury B.L. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2021-11-04 00:00:00.0; , .
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Source: Cancer Immunology, Immunotherapy : Cii, 2021-09-16 00:00:00.0; , .
EPub date: 2021-09-16 00:00:00.0.
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Authors: Sikavi D.R. , Nguyen L.H. , Haruki K. , Ugai T. , Ma W. , Wang D.D. , Thompson K.N. , Yan Y. , Branck T. , Wilkinson J.E. , et al. .
Source: Clinical And Translational Gastroenterology, 2021-08-01 00:00:00.0; 12(8), p. e00338.
EPub date: 2021-08-01 00:00:00.0.
PMID: 34333506
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Authors: Dai J. , Nishi A. , Tran N. , Yamamoto Y. , Dewey G. , Ugai T. , Ogino S. .
Source: Expert Review Of Molecular Diagnostics, 2021-07-26 00:00:00.0; , p. 1-18.
EPub date: 2021-07-26 00:00:00.0.
PMID: 34253130
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Authors: Nguyen L.H. , Cao Y. , Hur J. , Mehta R.S. , Sikavi D.R. , Wang Y. , Ma W. , Wu K. , Song M. , Giovannucci E.L. , et al. .
Source: Gastroenterology, 2021-07-14 00:00:00.0; , .
EPub date: 2021-07-14 00:00:00.0.
PMID: 34273347
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Authors: Väyrynen J.P. , Haruki K. , Väyrynen S.A. , Lau M.C. , Dias Costa A. , Borowsky J. , Zhao M. , Ugai T. , Kishikawa J. , Akimoto N. , et al. .
Source: Journal For Immunotherapy Of Cancer, 2021 Apr; 9(4), .
PMID: 33931472
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Authors: Borowsky J. , Haruki K. , Lau M.C. , Dias Costa A. , Väyrynen J.P. , Ugai T. , Arima K. , da Silva A. , Felt K. , Zhao M. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2021-02-25 00:00:00.0; , .
EPub date: 2021-02-25 00:00:00.0.
PMID: 33632927
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Opinion: Standardizing gene product nomenclature-a call to action.
Authors: Fujiyoshi K. , Bruford E.A. , Mroz P. , Sims C.L. , O'Leary T.J. , Lo A.W.I. , Chen N. , Patel N.R. , Patel K.P. , Seliger B. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2021-01-19 00:00:00.0; 118(3), .
PMID: 33408252
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Authors: Long L. , Yang W. , Liu L. , Tobias D.K. , Katagiri R. , Wu K. , Jin L. , Zhang F.F. , Luo X. , Liu X. , et al. .
Source: International Journal Of Cancer, 2020-12-19 00:00:00.0; , .
EPub date: 2020-12-19 00:00:00.0.
PMID: 33341092
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Authors: Akimoto N. , Ugai T. , Zhong R. , Hamada T. , Fujiyoshi K. , Giannakis M. , Wu K. , Cao Y. , Ng K. , Ogino S. .
Source: Nature Reviews. Clinical Oncology, 2020-11-20 00:00:00.0; , .
EPub date: 2020-11-20 00:00:00.0.
PMID: 33219329
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Authors: Mima K. , Kosumi K. , Baba Y. , Hamada T. , Baba H. , Ogino S. .
Source: Human Genetics, 2020-11-12 00:00:00.0; , .
EPub date: 2020-11-12 00:00:00.0.
PMID: 33180176
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Authors: Neumeyer S. , Hua X. , Seibold P. , Jansen L. , Benner A. , Burwinkel B. , Halama N. , Berndt S.I. , Phipps A.I. , Sakoda L.C. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2020-10-02 00:00:00.0; , .
EPub date: 2020-10-02 00:00:00.0.
PMID: 33008876
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Authors: Fujiyoshi K. , Väyrynen J.P. , Borowsky J. , Papke D.J. , Arima K. , Haruki K. , Kishikawa J. , Akimoto N. , Ugai T. , Lau M.C. , et al. .
Source: Ebiomedicine, 2020 Jul; 57, p. 102860.
EPub date: 2020-07-08 00:00:00.0.
PMID: 32652320
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