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In-vivo administration of histone deacetylase inhibitors does not impair natural killer cell function in HIV+ individuals.

ABSTRACT: OBJECTIVE:Histone deacetylase inhibitors (HDACi) have proven to induce HIV-RNA and antigen expression in resting CD4 T cells of antiretroviral therapy (ART)-treated HIV-infected individuals. However, to achieve viral eradication, immune clearance must follow latency reversal, and thus it is essential to understand the impact of latency reversal agents on immune function. DESIGN:Here we evaluate the impact of in-vivo administration of vorinostat (VOR) and panobinostat (PNB) during clinical trials on natural killer (NK) cell function and phenotype. METHODS:Cryopreserved peripheral blood mononuclear cells from HIV-positive participants receiving VOR (NCT01319383) or PNB (NCT01680094) were selected to assess the impact of the drugs on cell composition, activation, NK cell phenotype (CD16, NKG2D, NKp30, NKp46 and DNAM-1), cytotoxic activity (CD107a), and interferon (IFN)-? production. RESULTS:No impairment of NK cell function was observed during treatment with either VOR or PNB. An increase in the frequency of CD3CD56 NK cells was consistently observed. Interestingly, after VOR administration, NK cells increased expression of NKp46 and CD16, and showed improved degranulation and IFN-? production capacity. Moreover, taking together VOR and PNB samples, HIV DNA levels in CD4 cells were negatively correlated with NK cell frequency and NK cell expression of CD16. CONCLUSIONS:In-vivo treatment with HDACi does not have measurable negative effects on NK cell function, with some evidence of improved function in vitro. These results have important implications for potential combinatorial approaches to target HIV reservoirs, suggesting that the use of HDACis as a latency reversal agent could be paired with interventions to enhance NK cell activity or recruitment.

SUBMITTER: Garrido C

PROVIDER: S-EPMC6400302 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:Despite being subjected to high dose chemo and radiotherapy, glioblastoma (GBM) patients still encounter almost inevitable relapse due to the capability of tumor cells to disseminate and invade normal brain tissues. Moreover, the presence of a Cancer Stem Cell (CSC) subpopulation, already demonstrated to better resist and evade treatments, further frustrate potential therapeutic approaches. In this context, we previously demonstrated that GBM is characterized by a tightly regulated balance between the β-catenin cofactors TCF1 and TCF4, with high levels of TCF4 responsible for sustaining CSC in these tumors, thus supporting their aggressive features. Since Histone Deacetylase Inhibitors (HDI) have been reported to strongly reduce TCF4 levels in colon cancer cells, we hypothesized they could exert a similar therapeutic action also in GBM. Here, we treated primary GBM cultures with Trichostatin-A and Vorinostat, demonstrating their ability to strongly suppress the Wnt dependent pathways, thus promoting CSC differentiation, and concomitantly impairing GBM cell viability and proliferation. More interestingly, analysis of their molecular effects suggested a prominent HDI action against GBM cell motility/migration, that we demonstrated to be dependent on the inhibition of the RhoA-GTPase and interferon intracellular cascades. Our results suggest HDI as potential therapeutic agents in GBM through their action on multiple cancer hallmarks. Glioblastoma (GBM) is considered the deadliest brain tumor, with patients displaying a high incidence of relapse and a 3-year survival of only 3-5%. For these reasons, investigation of the molecular basis of the disease could provide novel targets for therapy and improve patient prognosis. Based on our previous data demonstrating that high levels of the transcription factor TCF4 (TCF7L2) sustain the aggressiveness and the stem cell features of these tumors, in this study we tested the ability of the histone deacetylase inhibitors (HDI) Trichostatin-A and Vorinostat to suppress TCF4 levels. We demonstrated that HDI treatment impairs proliferation and viability of GBM cells. Moreover, molecular analysis of HDI effects disclosed their ability to counteract tumor cell motility by affecting the RhoA-GTPase and the interferon pathways, supporting their further characterization as potential anti-GBM agents

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In-vivo administration of histone deacetylase inhibitors does not impair natural killer cell function in HIV+ individuals.

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