PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Li, Jie; Kaneda, Megan M.; Ma, Jun; Li, Ming; Patel, Kunal; Koga, Tomoyuki; Sarver, Aaron L.; Furnari, Frank B.; Xu, Beibei; Dhawan, Sanjay; Ning, Jianfang; Zhu, Hua; Wu, Anhua; You, Guoxiang; Jiang, Tao; Venteicher, Andrew S.; Rich, Jeremy; Glass, Christopher K.; Varner, Judith A.; Chen, Clark C.

doi:10.1101/2020.05.14.097121

Cited by 4 publications

(4 citation statements)

References 80 publications

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“…We find evidence in the literature supporting the effectiveness of these drug combinations. Li et al state that TMZ enhances the effect of TG100-115 on GBM cells and improves survival in mice [51]. Zhang et al show that the combination of LY2109761 and TMZ suppresses the tumor growth on T98G cell line.…”

Section: E Novel Predictionsmentioning

confidence: 99%

MatchMaker: A Deep Learning Framework for Drug Synergy Prediction

Kuru

Taştan

Cicek

2022

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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Drug combination therapies have been a viable strategy for the treatment of complex diseases such as cancer due to increased efficacy and reduced side effects. However, experimentally validating all possible combinations for synergistic interaction even with high-throughout screens is intractable due to vast combinatorial search space. Computational techniques can reduce the number of combinations to be evaluated experimentally by prioritizing promising candidates. We present MatchMaker that predicts drug synergy scores using drug chemical structure information and gene expression profiles of cell lines in a deep learning framework. For the first time, our model utilizes the largest known drug combination dataset to date, DrugComb. We compare the performance of Match-Maker with the state-of-the-art models and observe up to ∼ 15% correlation and ∼ 33% mean squared error (MSE) improvements over the next best method. We investigate the cell types and drug pairs that are relatively harder to predict and present novel candidate pairs. MatchMaker is built and available at https://github.com/tastanlab/matchmaker

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Section: E Novel Predictionsmentioning

confidence: 99%

MatchMaker: A Deep Learning Framework for Drug Synergy Prediction

Kuru

Taştan

Cicek

2022

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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“…Recently, numerous studies have reported that TAM/Ms regulation may be a potential therapy strategy in cases with GBM. A new report demonstrated that PI3Kγ inhibition could suppress TAM/M accumulation in glioblastoma microenvironment, and enhance the anti-neoplastic effects of temozolomide in glioblastoma cells ( 43 ). In addition, the deletion of HuR (an RNA regulator) in TAM/Ms could attenuate glioma growth ( 44 ).…”

Section: Role Of Tam/ms In Glioblastomamentioning

confidence: 99%

Crosstalk Between Tumor-Associated Microglia/Macrophages and CD8-Positive T Cells Plays a Key Role in Glioblastoma

Qiu

et al. 2021

Front. Immunol.

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Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.

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“…GAMs not only drive the formation of immunosuppressive ME but also induce GBM stemness and enhance in vitro and in vivo tumorigenicity. Furthermore, human microglia can promote TMZ resistance by the augmented expression of inflammatory IL-11, which activates the STAT3 (signal transducer and activator of transcription 3)-MYC pathway in tumor cells ( 36 ). STAT3 activation is implicated in therapy resistance independent of MGMT methylation and in shaping the tumor ME by promoting M2 polarization in a signaling loop of immunosuppression and immune escape.…”

Section: Introductionmentioning

confidence: 99%

“…STAT3 activation is implicated in therapy resistance independent of MGMT methylation and in shaping the tumor ME by promoting M2 polarization in a signaling loop of immunosuppression and immune escape. PI3K (PhosphatidylInositol 3-Kinase)-γ inhibition reduces IL-11 accumulation in the tumor ME, which mimics the TMZ response of the so-called “exceptional responders” whose tumors show a reduced trafficking and infiltration of GAMs ( 36 ). The connection between the chemotherapy response and microglia is similarly evident from the capacity of TMZ-resistant GBM cells to promote M2 polarization by increased levels of lncRNA (long noncoding RNA) SNHG15 (small nucleolar RNA host gene 15).…”

Section: Introductionmentioning

confidence: 99%

Revisiting the Immunological Aspects of Temozolomide Considering the Genetic Landscape and the Immune Microenvironment Composition of Glioblastoma

et al. 2021

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The microenvironment (ME) plays a critical role in causing glioblastoma (GBM) to be a moving and incurable target. The main features governing the interaction between cancer cells and the ME include dependency, promotion, and in rare cases, even competition. In the original Stupp protocol, the alkylating agent temozolomide (TMZ) is the first-line chemotherapy drug to treat GBM, and it is broadly used together or after radiotherapy. Some studies have described TMZ as an adjuvant to other therapeutic approaches including immunotherapy because of its ability to induce an immunogenic death of cancer cells. TMZ also exerts immunomodulatory effects on the tumor and immune ME. These findings support the coexistence of two circuits, i.e., one that subverts local immunosuppressive mechanisms and another that exerts a harmful influence on the peripheral immune response. A bias toward the latter can drive the failure of treatments based on the combination of chemotherapy and immunotherapy approaches. In this review, we will reanalyze how intrinsic and acquired resistance to TMZ impacts the immunomodulatory effects previously described by way of inducing a functional alteration of local immune cells and promoting immunosuppression and how different components of the immune ME, with particular attention to tumor-associated macrophages and microglia, can cause TMZ resistance to circumvent potential local immunogenic mechanisms.

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PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Cited by 4 publications

References 80 publications

MatchMaker: A Deep Learning Framework for Drug Synergy Prediction

MatchMaker: A Deep Learning Framework for Drug Synergy Prediction

Crosstalk Between Tumor-Associated Microglia/Macrophages and CD8-Positive T Cells Plays a Key Role in Glioblastoma

Revisiting the Immunological Aspects of Temozolomide Considering the Genetic Landscape and the Immune Microenvironment Composition of Glioblastoma

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