Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SAGE Publishing
2020-04-01
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| Series: | Therapeutic Advances in Medical Oncology |
| Online Access: | https://doi.org/10.1177/1758835920913798 |
| _version_ | 1819278622613045248 |
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| author | David W. Doo Selene Meza-Perez Angelina I. Londoño Whitney N. Goldsberry Ashwini A. Katre Jonathan D. Boone Dylana J. Moore Cindy T. Hudson Ilaria Betella Tyler R. McCaw Abhishek Gangrade Riyue Bao Jason J. Luke Eddy S. Yang Michael J. Birrer Dmytro Starenki Sara J. Cooper Donald J. Buchsbaum Lyse A. Norian Troy D. Randall Rebecca C. Arend |
| author_facet | David W. Doo Selene Meza-Perez Angelina I. Londoño Whitney N. Goldsberry Ashwini A. Katre Jonathan D. Boone Dylana J. Moore Cindy T. Hudson Ilaria Betella Tyler R. McCaw Abhishek Gangrade Riyue Bao Jason J. Luke Eddy S. Yang Michael J. Birrer Dmytro Starenki Sara J. Cooper Donald J. Buchsbaum Lyse A. Norian Troy D. Randall Rebecca C. Arend |
| author_sort | David W. Doo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T00:14:56Z |
| format | Article |
| id | doaj.art-9e744b8aa2274b79bb8a1c96027e50f5 |
| institution | Directory Open Access Journal |
| issn | 1758-8359 |
| language | English |
| last_indexed | 2024-12-24T00:14:56Z |
| publishDate | 2020-04-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Therapeutic Advances in Medical Oncology |
| spelling | doaj.art-9e744b8aa2274b79bb8a1c96027e50f52022-12-21T17:24:46ZengSAGE PublishingTherapeutic Advances in Medical Oncology1758-83592020-04-011210.1177/1758835920913798Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancerDavid W. DooSelene Meza-PerezAngelina I. LondoñoWhitney N. GoldsberryAshwini A. KatreJonathan D. BooneDylana J. MooreCindy T. HudsonIlaria BetellaTyler R. McCawAbhishek GangradeRiyue BaoJason J. LukeEddy S. YangMichael J. BirrerDmytro StarenkiSara J. CooperDonald J. BuchsbaumLyse A. NorianTroy D. RandallRebecca C. ArendBackground: 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.https://doi.org/10.1177/1758835920913798 |
| spellingShingle | David W. Doo Selene Meza-Perez Angelina I. Londoño Whitney N. Goldsberry Ashwini A. Katre Jonathan D. Boone Dylana J. Moore Cindy T. Hudson Ilaria Betella Tyler R. McCaw Abhishek Gangrade Riyue Bao Jason J. Luke Eddy S. Yang Michael J. Birrer Dmytro Starenki Sara J. Cooper Donald J. Buchsbaum Lyse A. Norian Troy D. Randall Rebecca C. Arend Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer Therapeutic Advances in Medical Oncology |
| title | Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer |
| title_full | Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer |
| title_fullStr | Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer |
| title_full_unstemmed | Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer |
| title_short | Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer |
| title_sort | inhibition of the wnt β catenin pathway enhances antitumor immunity in ovarian cancer |
| url | https://doi.org/10.1177/1758835920913798 |
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