title: Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women.
abstract: Background:Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.Methods:Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer-specific death associated with each composite score.Results:CTL and GZMB composite scores were positively correlated (r= 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, orBRAFmutation status. HRs (95% CI) were 0.53 (0.38-0.75;Ptrend= 0.0004) and 0.66 (0.51-0.86;Ptrend= 0.002) for all-cause death, respectively, and 0.30 (0.18-0.51;Ptrend< 0.0001) and 0.41 (0.27-0.63;Ptrend< 0.0001) for colorectal cancer-related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer-related death.Conclusions:Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.Impact:Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage.Cancer Epidemiol Biomarkers Prev; 26(4); 622-31. ©2016 AACR.
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota. prizm001@umn.edu.|University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Prizment
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lori S
authors.initials: LS
authors.lastname: Tillmans
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota.|University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.affiliation: Department of Epidemiology, University of Iowa, Iowa City, Iowa.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.affiliation: University Imaging Centers, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pengo
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Division of Environmental Health Sciences, University of Minnesota School of Public Health, Minneapolis, Minnesota.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Church
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota.|University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Anderson
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D005260:Female; D053804:Granzymes / Q000276:immunology*; D006801:Humans; D008137:Longitudinal Studies; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies
chemical_list: D014408:Biomarkers, Tumor; C509213:GZMB protein, human; D053804:Granzymes