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Grant Details

Grant Number: 5R01CA197350-05 Interpret this number
Primary Investigator: Gruber, Stephen
Organization: University Of Southern California
Project Title: The Epidemiology of Immune Responses in Colorectal Cancer
Fiscal Year: 2019
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Abstract

? DESCRIPTION (provided by applicant): The immune system plays a key role in regulating the development and progression of colorectal cancer (CRC), and tumor infiltration by T lymphocytes is a highly informative prognostic factor for CRC outcome. Advances in screening and treatment have substantially improved survival from CRC over the past decade, but clinical outcomes still vary widely among patients with tumors diagnosed at the same TNM stage, and disease relapse occurs in 20-30% of patients with localized cancer. This suggests that traditional prognostic factors, including stage and tumor infiltrating lymphocytes (TIL) quantified by classical means of expert pathology review under light microscopy, lack sufficient granularity to predict patient outcome and to guide the optimal treatment choice for many patients. TILs can trigger preferential lysis of cancer cells by recognizing enhanced expression of abnormally expressed antigens presented in the context of HLA molecules, but the host and tumor factors regulating this adaptive immune response in the tumor microenvironment remain largely unexplored. We propose to address these gaps in knowledge by studying the factors regulating the immune response in an existing, population- based epidemiologic study of 4,000 colorectal cancer cases with essentially perfect clinical annotation and follow-up. A new technical advance now permits the direct sequencing and quantification of the T cell receptor (TCR) repertoire that arises within CRC, providing an opportunity to gain fundamental mechanistic insight within an epidemiologic context. Our goal is to understand why adaptive immune responses differ so dramatically across colorectal cancers, and to harness this information to improve patient outcomes. Here, we hypothesize that clinical, epidemiologic and genetic factors regulate the strength and the quality of the host immune response, and that these factors contribute independently to prognosis. Further, we hypothesize that TIL quantity and TCR clonality in CRC tumors are independent prognostic factors. Combining an innovative high-throughput sequencing approach for TIL characterization (immunoSEQ), a genome-wide association study (GWAS) of genetic variation influencing lymphocyte infiltration in the TME, and a classical epidemiologic investigation of prognosis, we will comprehensively describe the epidemiology of the hostimmune response in tumors from 4,000 patients within a population-based case-control study of CRC in northern Israel. We will identify factors that regulate the host immune response to CRC on a population scale, and advance the current understanding of prognostic factors for CRC, through 3 specific aims. In Aim 1, we will quantify and characterize T cell infiltration in 4,000 primary colorectal cancers (CRCs) from the Molecular Epidemiology of Colorectal Cancer (MECC) study using traditional light microscopy and immunoSEQ. In Aim 2, we will investigate the association of classic epidemiologic variables, HLA locus-specific genetic variation, and genome-wide germline variation with quantitative metrics of the host immune response in 4,000 primary CRCs. In Aim 3, we will evaluate TIL quantity, clonality, and any newly-identified genetic/HLA alleles predictive of immune response as prognostic factors for overall and disease-free survival from CRC. Combining epidemiologic and genetic variables with quantitative and qualitative metrics of the host immune response in the tumor may reveal novel molecular and cellular signatures associated with immune-mediated, tissue-specific destruction.

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Publications

Red meat and processed meat intake and risk of colorectal cancer: a population-based case-control study.
Authors: Saliba W. , Rennert H.S. , Gronich N. , Gruber S.B. , Rennert G. .
Source: European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 2019 Jul; 28(4), p. 287-293.
PMID: 30640205
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer.
Authors: Bien S.A. , Su Y.R. , Conti D.V. , Harrison T.A. , Qu C. , Guo X. , Lu Y. , Albanes D. , Auer P.L. , Banbury B.L. , et al. .
Source: Human genetics, 2019 Apr; 138(4), p. 307-326.
EPub date: 2019-02-28.
PMID: 30820706
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Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.
Authors: Lu Y. , Kweon S.S. , Tanikawa C. , Jia W.H. , Xiang Y.B. , Cai Q. , Zeng C. , Schmit S.L. , Shin A. , Matsuo K. , et al. .
Source: Gastroenterology, 2019 Apr; 156(5), p. 1455-1466.
EPub date: 2018-12-06.
PMID: 30529582
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Shared heritability and functional enrichment across six solid cancers.
Authors: Jiang X. , Finucane H.K. , Schumacher F.R. , Schmit S.L. , Tyrer J.P. , Han Y. , Michailidou K. , Lesseur C. , Kuchenbaecker K.B. , Dennis J. , et al. .
Source: Nature communications, 2019-01-25; 10(1), p. 431.
EPub date: 2019-01-25.
PMID: 30683880
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Discovery of common and rare genetic risk variants for colorectal cancer.
Authors: Huyghe J.R. , Bien S.A. , Harrison T.A. , Kang H.M. , Chen S. , Schmit S.L. , Conti D.V. , Qu C. , Jeon J. , Edlund C.K. , et al. .
Source: Nature genetics, 2019 01; 51(1), p. 76-87.
EPub date: 2018-12-03.
PMID: 30510241
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
Authors: Schmit S.L. , Edlund C.K. , Schumacher F.R. , Gong J. , Harrison T.A. , Huyghe J.R. , Qu C. , Melas M. , Van Den Berg D.J. , Wang H. , et al. .
Source: Journal of the National Cancer Institute, 2019-02-01; 111(2), p. 146-157.
PMID: 29917119
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A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster.
Authors: McDonnell K.J. , Chemler J.A. , Bartels P.L. , O'Brien E. , Marvin M.L. , Ortega J. , Stern R.H. , Raskin L. , Li G.M. , Sherman D.H. , et al. .
Source: Nature chemistry, 2018 08; 10(8), p. 873-880.
EPub date: 2018-06-18.
PMID: 29915346
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Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer.
Authors: Neumeyer S. , Banbury B.L. , Arndt V. , Berndt S.I. , Bezieau S. , Bien S.A. , Buchanan D.D. , Butterbach K. , Caan B.J. , Campbell P.T. , et al. .
Source: British journal of cancer, 2018 06; 118(12), p. 1639-1647.
EPub date: 2018-05-24.
PMID: 29795306
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T-Cell Transfer Therapy Targeting Mutant KRAS.
Authors: Maoz A. , Rennert G. , Gruber S.B. .
Source: The New England journal of medicine, 2017-02-16; 376(7), p. e11.
PMID: 28207209
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Tumor-Infiltrating Lymphocytes, Crohn's-Like Lymphoid Reaction, and Survival From Colorectal Cancer.
Authors: Rozek L.S. , Schmit S.L. , Greenson J.K. , Tomsho L.P. , Rennert H.S. , Rennert G. , Gruber S.B. .
Source: Journal of the National Cancer Institute, 2016 08; 108(8), .
EPub date: 2016-05-12.
PMID: 27172903
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