Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome
CANCER IMMUNOLOGY RESEARCH
Authors: Charbonneau, Bridget; Moysich, Kirsten B.; Kalli, Kimberly R.; Oberg, Ann L.; Vierkant, Robert A.; Fogarty, Zachary C.; Block, Matthew S.; Maurer, Matthew J.; Goergen, Krista M.; Fridley, Brooke L.; Cunningham, Julie M.; Rider, David N.; Preston, Claudia; Hartmann, Lynn C.; Lawrenson, Kate; Wang, Chen; Tyrer, Jonathan; Song, Honglin; defazio, Anna; Johnatty, Sharon E.; Doherty, Jennifer A.; Phelan, Catherine M.; Sellers, Thomas A.; Ramirez, Starr M.; Vitonis, Allison F.; Terry, Kathryn L.; Van den Berg, David; Pike, Malcolm C.; Wu, Anna H.; Berchuck, Andrew; Gentry-Maharaj, Aleksandra; Ramus, Susan J.; Diergaarde, Brenda; Shen, Howard; Jensen, Allan; Menkiszak, Janusz; Cybulski, Cezary; Lubinski, Jan; Ziogas, Argyrios; Rothstein, Joseph H.; McGuire, Valerie; Sieh, Weiva; Lester, Jenny; Walsh, Christine; Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn; Garcia-Closas, Montserrat; Yang, Hannah; Brinton, Louise A.; Spiewankiewicz, Beata; Rzepecka, Iwona K.; Dansonka-Mieszkowska, Agnieszka; Seibold, Petra; Rudolph, Anja; Paddock, Lisa E.; Orlow, Irene; Lundvall, Lene; Olson, Sara H.; Hogdall, Claus K.; Schwaab, Ira; Du Bois, Andreas; Harter, Philipp; Flanagan, James M.; Brown, Robert; Paul, James; Ekici, Arif B.; Beckmann, MatthiasW.; Hein, Alexander; Eccles, Diana; Lurie, Galina; Hays, Laura E.; Bean, Yukie T.; Pejovic, Tanja; Goodman, Marc T.; Campbell, Ian; Fasching, Peter A.; Konecny, Gottfried; Kaye, Stanley B.; Heitz, Florian; Hogdall, Estrid; Bandera, Elisa V.; Chang-Claude, Jenny; Kupryjanczyk, Jolanta; Wentzensen, Nicolas; Lambrechts, Diether; Karlan, Beth Y.; Whittemore, Alice S.; Culver, Hoda Anton; Gronwald, Jacek; Levine, Douglas A.; Kjaer, Susanne K.; Menon, Usha; Schildkraut, Joellen M.; Pearce, Celeste Leigh; Cramer, Daniel W.; Rossing, Mary Anne; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Gayther, Simon A.; Ness, Roberta B.; Odunsi, Kunle; Sucheston, Lara E.; Knutson, Keith L.; Goode, Ellen L.
Abstract
The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 x 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 x 10(-5)), rs2476491 (HR, 1.40; 95% CI, 1.19-1.64; P = 5.6 x 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 x 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 x 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. (C) 2014 AACR.
Regulatory effects of IL-15 on allergen-induced airway obstruction
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Authors: Venkateshaiah, Sathisha Upparahalli; Zhu, Xiang; Rajavelu, Priya; Niranjan, Rituraj; Manohar, Murli; Verma, Alok K.; Lasky, Joseph A.; Mishra, Anil
Abstract
Background: Airway obstruction is a physiologic feature of asthma, and IL-15 might have an important role in asthma pathogenesis. Objective: We tested the hypothesis that regulation of IL-15 is critical for preservation of allergen-induced airway hyperresponsiveness (AHR), airway resistance, and compliance in response to methacholine. Methods: Airway inflammation, AHR, resistance, and compliance were assessed in Il15 gene-deficient mice and IL-15-overexpressing mice in an allergen-induced murine model of asthma. We assessed eosinophil numbers by using anti-major basic protein immunostaining, goblet cell hyperplasia by using periodic acid-Schiff staining, and cytokine and chemokine levels by performing quantitative PCR and ELISA. Results: We made a novel observation that IL-15 deficiency promotes baseline airway resistance in naive mice. Moreover, rIL-15 delivery to the lung downregulates expression of proinflammatory cytokines and improves allergen-induced AHR, airway resistance, and compliance. These observations were further validated in doxycycline-inducible CC10-IL-15 bitransgenic mice. Doxycycline-exposed, Aspergillus species extract-challenged CC10-IL-15 bitransgenic mice exhibited significantly reduced levels of proinflammatory cytokines (IL-4, IL-5, and IL-13) and decreased goblet cell hyperplasia. Airway obstruction, including AHR and airway resistance, was diminished in allergen-challenged doxycycline-exposed compared with non-doxycycline-exposed CC10-IL-15 bitransgenic mice. Mechanistically, we observed that IL-15-mediated protection of airway obstruction is associated with induced IFN-gamma- and IL-10-producing regulatory CD4(+) CD25(+) forkhead box p3 (Foxp3)(+) T cells. Additionally, we found that a human IL-15 agonist (ALT-803) improved airway resistance and compliance in an experimental asthma model. Conclusion: We report our novel finding that IL-15 has a potent inhibitory effect on the airway obstruction that occurs in response to environmental allergens.
COA
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