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Grant Details

Grant Number: 5R01CA248857-04 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: 2022


Abstract

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.



Publications

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 Oct; 19(10), p. 656-673.
EPub date: 2022-09-06.
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; , .
EPub date: 2022-07-12.
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; 14(7), .
EPub date: 2022-04-02.
PMID: 35406583
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Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.
Authors: Ugai T. , Väyrynen J.P. , Lau M.C. , Borowsky J. , Akimoto N. , Väyrynen S.A. , Zhao M. , Zhong R. , Haruki K. , Dias Costa A. , et al. .
Source: Cancer immunology, immunotherapy : CII, 2022 Apr; 71(4), p. 933-942.
EPub date: 2021-09-16.
PMID: 34529108
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Spatial Organization and Prognostic Significance of NK and NKT-like Cells via Multimarker Analysis of the Colorectal Cancer Microenvironment.
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, 2022 02; 10(2), p. 215-227.
EPub date: 2021-12-22.
PMID: 34937729
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Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates.
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; 114(1), p. 68-77.
PMID: 34264325
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Desmoplastic Reaction, Immune Cell Response, and Prognosis in Colorectal Cancer.
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.
PMID: 35392092
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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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Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis.
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, 2022 01; 31(1), p. 210-220.
EPub date: 2021-11-04.
PMID: 34737207
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Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma.
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; 27(24), p. 6622-6637.
EPub date: 2021-07-20.
PMID: 34285063
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The Sulfur Microbial Diet Is Associated With Increased Risk of Early-Onset Colorectal Cancer Precursors.
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 11; 161(5), p. 1423-1432.e4.
EPub date: 2021-07-14.
PMID: 34273347
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Revisiting social MPE: an integration of molecular pathological epidemiology and social science in the new era of precision medicine.
Authors: Dai J. , Nishi A. , Tran N. , Yamamoto Y. , Dewey G. , Ugai T. , Ogino S. .
Source: Expert review of molecular diagnostics, 2021 Sep; 21(9), p. 869-886.
EPub date: 2021-07-26.
PMID: 34253130
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The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men.
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; 12(8), p. e00338.
EPub date: 2021-08-01.
PMID: 34333506
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Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment.
Authors: Borowsky J. , Haruki K. , Lau M.C. , Dias Costa A. , Väyrynen J.P. , Ugai T. , Arima K. , da Silva A. , Felt K.D. , Zhao M. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2021-05-15; 27(10), p. 2816-2826.
EPub date: 2021-02-25.
PMID: 33632927
Related Citations

The microbiome, genetics, and gastrointestinal neoplasms: the evolving field of molecular pathological epidemiology to analyze the tumor-immune-microbiome interaction.
Authors: Mima K. , Kosumi K. , Baba Y. , Hamada T. , Baba H. , Ogino S. .
Source: Human genetics, 2021 May; 140(5), p. 725-746.
EPub date: 2020-11-12.
PMID: 33180176
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Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment.
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 04; 9(4), .
PMID: 33931472
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Rising incidence of early-onset colorectal cancer - a call to action.
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, 2021 04; 18(4), p. 230-243.
EPub date: 2020-11-20.
PMID: 33219329
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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; 118(3), .
PMID: 33408252
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Dietary intake of branched-chain amino acids and survival after colorectal cancer diagnosis.
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; , .
EPub date: 2020-12-19.
PMID: 33341092
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Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis.
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 12; 29(12), p. 2719-2728.
EPub date: 2020-10-02.
PMID: 33008876
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Tumour budding, poorly differentiated clusters, and T-cell response in colorectal cancer.
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.
PMID: 32652320
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