title: Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer.
abstract: The immune system constitutes one of the host factors modifying outcomes in ovarian cancer. Regulatory T cells (Tregs) are believed to be a major factor in preventing the immune response from destroying ovarian cancers. Understanding mechanisms that regulate Tregs in the tumor microenvironment could lead to the identification of novel targets aimed at reducing their influence. In this study, we used immunofluorescence-based microscopy to enumerate Tregs, total CD4 T cells, and CD8(+) cytotoxic T cells in fresh frozen tumors from over 400 patients with ovarian cancer (>80 % high-grade serous). We sought to determine whether Tregs were associated with survival and genetic variation in 79 genes known to influence Treg induction, trafficking, or function. We used Cox regression, accounting for known prognostic factors, to estimate hazard ratios (HRs) associated with T cell counts and ratios. We found that the ratios of CD8 T cells and total CD4 T cells to Tregs were associated with improved overall survival (CD8/Treg HR 0.84, p = 0.0089; CD4/Treg HR 0.88, p = 0.046) and with genetic variation in IL-10 (p = 0.0073 and 0.01, respectively). In multivariate analyses, the associations between the ratios and overall survival remained similar (IL-10 and clinical covariate-adjusted CD8/Treg HR 0.85, p = 0.031; CD4/Treg HR 0.87, p = 0.093), suggesting that this association was not driven by variation in IL-10. Thus, integration of novel tumor phenotyping measures with extensive clinical and genetic information suggests that the ratio of T cells to Tregs may be prognostic of outcome in ovarian cancer, regardless of inherited genotype in genes related to Tregs.
authors: Cancer Vaccines and Immune Therapies Program, The Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, FL, USA. knutson.keith@mayo.edu.|Department of Immunology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA. knutson.keith@mayo.edu.
authors: Keith L
authors: KL
authors: Knutson
authors: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors: Matthew J
authors: MJ
authors: Maurer
authors: Department of Immunology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors: Claudia C
authors: CC
authors: Preston
authors: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Kirsten B
authors: KB
authors: Moysich
authors: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors: Krista
authors: K
authors: Goergen
authors: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors: Kieran M
authors: KM
authors: Hawthorne
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors: Julie M
authors: JM
authors: Cunningham
authors: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Kunle
authors: K
authors: Odunsi
authors: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors: Lynn C
authors: LC
authors: Hartmann
authors: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors: Kimberly R
authors: KR
authors: Kalli
authors: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors: Ann L
authors: AL
authors: Oberg
authors: Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. egoode@mayo.edu.
authors: Ellen L
authors: EL
authors: Goode
mesh_terms: D016516:CD4-CD8 Ratio; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D018655:Lymphocyte Count; D018613:Microscopy, Confocal; D009375:Neoplasms, Glandular and Epithelial / Q000175:diagnosis* / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: D016753:Interleukin-10
keywords: CD8; Immune suppression; Treg; Tumor microenvironment