Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1

McCaw, Tyler R.; Li, Mei; Starenki, Dmytro; Liu, Mingyong; Cooper, Sara J.; Arend, Rebecca C.; Forero, Andres; Buchsbaum, Donald J.; Randall, Troy D.

doi:10.1007/s00262-019-02430-9

Cited by 35 publications

(23 citation statements)

References 42 publications

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“…These changes may indicate an improved ability of Tbet single‐positive CD8 T cells to traffic into or persist in the tumor mass following class I HDAC inhibition. Indeed, class I HDAC inhibition can augment accumulation of IFNγ‐producing CD8 T cells within solid tumors 29 . A finding consistent with increasing numbers of Tbet‐positive CD8 T cells within tumors following class I HDAC inhibition, as Tbet regulates IFNγ production 30 …”

Section: Discussionmentioning

confidence: 88%

“…Collectively, our data suggests that class I HDAC inhibition destabilizes suppressive networks within ovarian tumors, shifting the TME toward one more favorable for anti‐tumor immunity. Additional interventions providing a “second hit” to these suppressive populations or blocking inhibitory signaling could further promote CD8 T cell responses and unleash the potential of immunotherapy in this hostile environment 29,37 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Entinostat (Ent, MS-275) is a synthetic benzamide derivative HDACi that has a strong immunomodulatory effect in BC ( Christmas et al, 2018 ; McCaw et al, 2019 ). Moreover, Ent treatment reverses the EMT and the tumor-initiating cell phenotype, which reduces tumorigenesis and metastasis ( Shah et al, 2014 ; Schech A. et al, 2015 ).…”

Section: Hm-associated Bc Therapymentioning

confidence: 99%

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way

Sui

et al. 2021

Front. Cell Dev. Biol.

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Histone modifications (HMs) contribute to maintaining genomic stability, transcription, DNA repair, and modulating chromatin in cancer cells. Furthermore, HMs are dynamic and reversible processes that involve interactions between numerous enzymes and molecular components. Aberrant HMs are strongly associated with tumorigenesis and progression of breast cancer (BC), although the specific mechanisms are not completely understood. Moreover, there is no comprehensive overview of abnormal HMs in BC, and BC therapies that target HMs are still in their infancy. Therefore, this review summarizes the existing evidence regarding HMs that are involved in BC and the potential mechanisms that are related to aberrant HMs. Moreover, this review examines the currently available agents and approved drugs that have been tested in pre-clinical and clinical studies to evaluate their effects on HMs. Finally, this review covers the barriers to the clinical application of therapies that target HMs, and possible strategies that could help overcome these barriers and accelerate the use of these therapies to cure patients.

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“…For example, histone deacetylase inhibitors (HDACi) have been implemented within tumor-targeting particles showing significant inhibitory effects on tumor growth ( Bertrand et al, 2019 ; Lee S. Y. et al, 2019 ). Studies evaluating the effects on the TIME of targeted HDACi therapy should be encouraged after the effects observed by selective HDACi in an NP-free treatment ( McCaw et al, 2019 ).…”

Section: Nanotechnologies For Therapeutic Deliverymentioning

confidence: 99%

Nanoparticle-Based Therapies for Turning Cold Tumors Hot: How to Treat an Immunosuppressive Tumor Microenvironment

Giustarini

Pavesi

Adriani

2021

Front. Bioeng. Biotechnol.

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Nanotechnologies are rapidly increasing their role in immuno-oncology in line with the need for novel therapeutic strategies to treat patients unresponsive to chemotherapies and immunotherapies. The tumor immune microenvironment (TIME) has emerged as critical for tumor classification and patient stratification to design better treatments. Notably, the tumor infiltration of effector T cells plays a crucial role in antitumor responses and has been identified as the primary parameter to define hot, immunosuppressed, excluded, and cold tumors. Organic and inorganic nanoparticles (NPs) have been applied as carriers of new targeted therapies to turn cold or altered (i.e., immunosuppressed or excluded) tumors into more therapeutically responsive hot tumors. This mini-review discusses the significant advances in NP-based approaches to turn immunologically cold tumors into hot ones.

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Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1

Cited by 35 publications

References 42 publications

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

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

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way

Nanoparticle-Based Therapies for Turning Cold Tumors Hot: How to Treat an Immunosuppressive Tumor Microenvironment

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