Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma

Liu, Zengjin; Han, Houxiang; He, Xin; Li, Shouwei; Wu, Chenxing; Yu, Chunjiang; Wang, Shengdian

doi:10.3892/ol.2016.4142

Cited by 85 publications

(71 citation statements)

References 28 publications

(30 reference statements)

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“…Five of the samples showed TIM-3–positive lymphocytes, four revealed a tumor cell staining pattern, and two were suspicious for TIM-3 positivity on microglia or other unidentified lysosome-containing immune cells. The IHC results are evidence that TIM-3 is expressed in human glioblastoma multiforme, and taken together with studies confirming Gal-9 expression on glioma tumor cells (14), these findings suggest that TIM-3 blockade may be an effective immunotherapeutic strategy in glioblastoma multiforme and provide a rationale for clinical translation of anti-TIM-3 therapies.…”

Section: Discussionsupporting

confidence: 52%

“…However, the presence of TIM-3 in human glioblastoma multiforme has not yet been clearly confirmed by IHC. A recent study by Liu and colleagues found that Gal-9 (the activating ligand for TIM-3) was expressed at increased level in glioma patients’ brain tissues as compared with noncancerous tissue from control patients (14). Furthermore, Gal-9 expression was significantly higher in grade 4 gliomas than in lower grade gliomas (grades 2–3), and levels of expression were associated with TIM-3 expression on CD4 and CD8 TILs.…”

Section: Discussionmentioning

confidence: 99%

“…However, clinical studies have demonstrated TIM-3 expression to be significantly elevated on both circulating blood lymphocytes and TILs in glioma patients. This expression was found to be positively correlated with glioma grade and negatively correlated with Karnofsky performance status score (13, 14). Using our glioma model, we hypothesized that dual blockade of PD-1 and TIM-3 would result in a more robust antiglioma immune response and improved survival compared with either antibody alone.…”

Section: Introductionmentioning

confidence: 98%

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Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas

Kim

Patel

Mangraviti

et al. 2017

Clinical Cancer Research

386

323

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Purpose Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. Experimental Design C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. Results Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti- TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. Conclusions This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas

Kim

Patel

Mangraviti

et al. 2017

Clinical Cancer Research

386

323

View full text Add to dashboard Cite

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“…Considering that ligands of these proteins are overexpressed in GBM cells, i.e. PD-L1 45 , galectin-9 46 , they constitute valuable targets to overcome the immunosuppressive nature of GBM and improve the efficacy of immunotherapeutic strategies for GBM.…”

Section: Introductionmentioning

confidence: 99%

Recent advances and future of immunotherapy for glioblastoma

Kamran

Calinescu

Candolfi

et al. 2016

Expert Opinion on Biological Therapy

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Introduction Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. Areas covered Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. Expert opinion Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.

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“…Indeed, the available results suggest that galectin-9 expression is frequently altered when comparing tumor tissue with normal tissue (29). In addition, one study supports the hypothesis that galectin-9 is involved in several aspects of tumor progression (30).…”

Section: Discussionmentioning

confidence: 75%

miR-455-5p functions as a potential oncogene by targeting galectin-9 in colon cancer

et al. 2017

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Abstract.Although there is evidence that galectin-9 is a critical factor in health and disease, the upstream regulatory microRNA (miRNA or miR) of the protein remains poorly defined. miR-455-5p is characterized as a tumor-associated miRNA in cancer research. However, the actual role of miR-455-5p with respect to inhibiting or promoting tumorigenesis in colon cancer is unclear. The present study aimed to investigate the expression, role and target regulation association of galectin-9 and miR-455-5p in colon cancer. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were used for the detection of the expression levels of galectin-9 and miRNAs. Cell Counting kit-8 test was used for the evaluation of cell proliferation, while flow cytometry was used for cell apoptosis analysis. A potential interaction between galectin-9 and miR-455-5p was predicted by target prediction programs and confirmed by luciferase assay and transfection with miRNA mimics. The present study revealed that elevated expression of galectin-9 and miR-455-5p in colon cancer was associated with HT29 cell proliferation and apoptosis. Furthermore, the present study demonstrated that miR-455-5p reduced galectin-9 expression by directly targeting its 3'-untranslated region. These data suggest that miR-455-5p functions as a potential oncogene in colon cancer by targeting galectin-9.

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Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma

Cited by 85 publications

References 28 publications

Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas

Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas

Recent advances and future of immunotherapy for glioblastoma

miR-455-5p functions as a potential oncogene by targeting galectin-9 in colon cancer

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