Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer.

Autor:	Doo DW; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Meza-Perez S; Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA., Londoño AI; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Goldsberry WN; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Katre AA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Boone JD; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Moore DJ; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Hudson CT; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Betella I; Comprehensive Cancer Center, University of Alabama at Birmingham, AL, USA., McCaw TR; Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA., Gangrade A; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Bao R; Department of Pediatrics, University of Chicago School of Medicine, Chicago, IL, USA., Luke JJ; Department of Medicine, University of Chicago School of Medicine, Chicago, IL, USA., Yang ES; Comprehensive Cancer Center, University of Alabama at Birmingham, AL, USA., Birrer MJ; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Starenki D; Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA., Cooper SJ; Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA., Buchsbaum DJ; Comprehensive Cancer Center, University of Alabama at Birmingham, AL, USA., Norian LA; Comprehensive Cancer Center, University of Alabama at Birmingham, AL, USA., Randall TD; Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA., Arend RC; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Alabama at Birmingham, 619 19th Street South, 176F Rm 10250, Birmingham, AL 35249, USA.
Jazyk:	angličtina
Zdroj:	Therapeutic advances in medical oncology [Ther Adv Med Oncol] 2020 Apr 14; Vol. 12, pp. 1758835920913798. Date of Electronic Publication: 2020 Apr 14 (Print Publication: 2020).
DOI:	10.1177/1758835920913798
Abstrakt:	Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models. Methods: Human ovarian cancer cells were treated with WNT974 in vitro . RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and β-TCR repertoire analysis were used to determine the immune response. Results: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8 + T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4 + and CD8 + T cells. Treatment also decreased the expression of inhibitory receptors on CD8 + T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire. Conclusions: These findings suggest that inhibiting the Wnt/β-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel. Competing Interests: Conflict of interest statement: JJL is a consultant to and receives clinical trial research support from Novartis. The remaining authors declare no potential conflicts of interest. (© The Author(s), 2020.)
Databáze:	MEDLINE
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