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Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer.


ABSTRACT:

Objective

Patients with epithelial ovarian cancer (EOC) typically present with late-stage disease, posing a significant challenge to treatment. Although taxane and platinum-based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing. Here, we tested whether class I HDAC inhibition can promote anti-tumor T cell responses in a spontaneous and nonspontaneous murine model of EOC.

Methods

We used the spontaneous Tg-MISIIR-Tag and nonspontaneous ID8 models of murine ovarian cancer to test this hypothesis. Whole tumor transcriptional changes were assessed using the nCounter PanCancer Mouse Immune Profiling Panel. Changes in select protein expression of regulatory and effector T cells were measured by flow cytometry.

Results

We found that treatment with the class I HDAC inhibitor entinostat upregulated pathways and genes associated with CD8 T cell cytotoxic function, while downregulating myeloid derived suppressor cell chemoattractants. Suppressive capacity of regulatory T cells within tumors and associated ascites was significantly reduced, reversing the CD8-Treg ratio.

Conclusions

Our findings suggest class I HDAC inhibition can promote activation of intratumoral CD8 T cells, potentially by compromising suppressive networks within the EOC tumor microenvironment. In this manner, class I HDAC inhibition might render advanced-stage EOC susceptible to immunotherapeutic treatment modalities.

SUBMITTER: McCaw TR 

PROVIDER: S-EPMC7877343 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer.

McCaw Tyler R TR   Goel Nidhi N   Brooke Dewey J DJ   Katre Ashwini A AA   Londoño Angelina I AI   Smith Haller J HJ   Randall Troy D TD   Arend Rebecca C RC  

Cancer medicine 20201224 2


<h4>Objective</h4>Patients with epithelial ovarian cancer (EOC) typically present with late-stage disease, posing a significant challenge to treatment. Although taxane and platinum-based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in  ...[more]

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