Dataset Information

HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer.

ABSTRACT: ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of CD274, the gene encoding PD-L1. Reduced tumor burden and improved survival were observed in ARID1Aflox/flox/PIK3CAH1047R OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune checkpoint blockade as a result of activation and increased presence of IFN?-positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell-dependent manner, as depletion of CD8+ T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune checkpoint blockade represents a potential treatment strategy for ARID1A-mutated cancers. SIGNIFICANCE: These findings offer a mechanistic rationale for combining epigenetic modulators and existing immunotherapeutic interventions against a disease that has been so far resistant to checkpoint blockade as a monotherapy.See related commentary by Prokunina-Olsson, p. 5476.

SUBMITTER: Fukumoto T

PROVIDER: S-EPMC6825538 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer.

Fukumoto Takeshi T Fatkhutdinov Nail N Zundell Joseph A JA Tcyganov Evgenii N EN Nacarelli Timothy T Karakashev Sergey S Wu Shuai S Liu Qin Q Gabrilovich Dmitry I DI Zhang Rugang R

Cancer research 20190716 21

<i>ARID1A,</i> encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of <i>ARID1A</i>-mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-ina ...[more]

PMID: 31311810

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Project description:Simple Summary Although immune checkpoint blockade has yielded unprecedented and durable responses in cancer patients, the efficacy of this treatment remains limited. Radiation therapy can induce immunogenic cell death that contributes to the local efficacy of irradiation. However, radiation-induced systemic responses are scarce. Studies combining radiation with checkpoint inhibitors suggest a synergistic potential of this strategy. In this review, we focused on parameters that can be optimized to enhance the anti-tumor immune response that results from this association, in order to achieve data on dose, fractionation, target volume, lymph nodes sparing, radiation particles, and other immunomodulatory agents. These factors should be considered in future trials for better clinical outcomes. To this end, we discussed the main preclinical and clinical data available to optimize the efficacy of the treatment combination. Abstract Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

Project description:BACKGROUND:PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS:The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. RESULTS:The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-? level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-? induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-?-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-? level. By combining the relative expression of the listed IFN-?-induced genes, IFN-? score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. CONCLUSION:Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-? is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-? score aggregated from the expressions of the listed IFN-?-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

Dataset Information

HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer.

Publications

HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer.

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