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No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

ABSTRACT: Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.

SUBMITTER: Sucheston-Campbell LE

PROVIDER: S-EPMC5500198 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

Sucheston-Campbell Lara E LE Cannioto Rikki R Clay Alyssa I AI Etter John Lewis JL Eng Kevin H KH Liu Song S Battaglia Sebastiano S Hu Qiang Q Szender J Brian JB Minlikeeva Albina A Joseph Janine M JM Mayor Paul P Abrams Scott I SI Segal Brahm H BH Wallace Paul K PK Soh Kah Teong KT Zsiros Emese E Anton-Culver Hoda H Bandera Elisa V EV Beckmann Matthias W MW Berchuck Andrew A Bjorge Line L Bruegl Amanda A Campbell Ian G IG Campbell Shawn Patrice SP Chenevix-Trench Georgia G Cramer Daniel W DW Dansonka-Mieszkowska Agnieszka A Dao Fanny F Diergaarde Brenda B Doerk Thilo T Doherty Jennifer A JA du Bois Andreas A Eccles Diana D Engelholm Svend Aage SA Fasching Peter A PA Gayther Simon A SA Gentry-Maharaj Aleksandra A Glasspool Rosalind M RM Goodman Marc T MT Gronwald Jacek J Harter Philipp P Hein Alexander A Heitz Florian F Hillemmanns Peter P Høgdall Claus C Høgdall Estrid V S EV Huzarski Tomasz T Jensen Allan A Johnatty Sharon E SE Jung Audrey A Karlan Beth Y BY Klapdor Reudiger R Kluz Tomasz T Konopka Bożena B Kjær Susanne Krüger SK Kupryjanczyk Jolanta J Lambrechts Diether D Lester Jenny J Lubiński Jan J Levine Douglas A DA Lundvall Lene L McGuire Valerie V McNeish Iain A IA Menon Usha U Modugno Francesmary F Ness Roberta B RB Orsulic Sandra S Paul James J Pearce Celeste Leigh CL Pejovic Tanja T Pharoah Paul P Ramus Susan J SJ Rothstein Joseph J Rossing Mary Anne MA Rübner Matthias M Schildkraut Joellen M JM Schmalfeldt Barbara B Schwaab Ira I Siddiqui Nadeem N Sieh Weiva W Sobiczewski Piotr P Song Honglin H Terry Kathryn L KL Van Nieuwenhuysen Els E Vanderstichele Adriaan A Vergote Ignace I Walsh Christine S CS Webb Penelope M PM Wentzensen Nicolas N Whittemore Alice S AS Wu Anna H AH Ziogas Argyrios A Odunsi Kunle K Chang-Claude Jenny J Goode Ellen L EL Moysich Kirsten B KB

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20160927 3

<b>Background:</b> The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.<b>Methods: ...[more]

PMID: 27677730

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Project description:The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1tm1Mom/J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice (p = 0.004) and in B6.129S7-Rag1tm1Mom/J mice (p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p ≤ 0.02) and monocytic MDSC (p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 (p = 0.01-median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88tm1.1Defr/J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro. Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

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No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

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No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

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