Targeting the PD-1/PD-L1 pathway in glioblastoma multiforme: Preclinical evidence and clinical interventions

Maghrouni, Abolfazl; Givari, Maryam; Jalili‐Nik, Mohammad; Mollazadeh, Hamid; Bibak, Bahram; Sadeghi, Mohammad Montazami; Afshari, Amir R.; Johnston, Thomas P.; Sahebkar, Amirhossein

doi:10.1016/j.intimp.2021.107403

Cited by 33 publications

(22 citation statements)

References 149 publications

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“…However, the expressions of LAG-3, CD47, and TIGIT were also compared between highand low-m6A score groups, and did not show significant differences. PD-1/PD-L1 serves as the major immune checkpoint due to its efficacy in highly aggressive tumors through the negative regulation of T-cell-mediated immune response (37). Activation of the PD-1/PD-L1 axis is a key factor in the immunosuppression of the TME.…”

Section: Discussionmentioning

confidence: 99%

Identification of an N6-methyladenosine (m6A)-related signature associated with clinical prognosis, immune response, and chemotherapy in primary glioblastomas

Cai¹,

Zhang²,

Liu³

et al. 2021

Ann Transl Med

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Background: N6-methyladenosine (m6A) RNA methylation regulators play crucial role in tumorigenicity and progression. However, their biological significance in primary glioblastomas (GBM) has not been fully elucidated.Methods: In the present study, we evaluated the 22 m6A RNA regulators using the integrated data of primary GBM samples from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. The different m6A modification patterns and m6A-related gene signature in primary GBM were distinguished by using principal component analysis. Single-sample gene set enrichment analysis was introduced to assess the relative level of immune infiltration. Gene set variation analysis was performed to calculate the enrichment score of the signaling pathways for different clusters. An m6A scoring scheme was established to evaluate the m6A modification pattern in individual tumors in order to predict prognosis and evaluate tumor microenvironment (TME) cell infiltration, immune response, and chemotherapy effect in primary GBM.Results: Two distinct m6A modification subgroups associated with different clinical features and biological pathways were identified among the 371 primary GBM. Based on 132 prognostic m6A phenotype-related differentially expressed genes (DEGs) between 2 m6A cluster subgroups, an m6A scoring model was constructed to assess the m6A modification pattern in individual tumors. The high-m6A score group was associated with better prognosis and immune response and worse chemotherapy effect. Conclusions:The findings of the present study indicate the potential role of m6A modification in primary GBM, which will help enhance our understanding of TME characteristics, predict clinical prognosis, and provide important insight into effective immunotherapy and chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Identification of an N6-methyladenosine (m6A)-related signature associated with clinical prognosis, immune response, and chemotherapy in primary glioblastomas

Cai¹,

Zhang²,

Liu³

et al. 2021

Ann Transl Med

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“…24,25 Total surgical resection accompanied by radiotherapy and concurrent chemotherapy with alkylating agent TMZ remains the primary care line, extending patients' survival by just 2 months in total. 26,27 Novel therapeutic strategies that boost clinical outcomes are therefore desperately needed. 28 The present study assessed Zerumbone to suppress GBM cancer cell development in vitro.…”

Section: Discussionmentioning

confidence: 99%

Zerumbone, a ginger sesquiterpene, inhibits migration, invasion, and metastatic behavior of human malignant glioblastoma multiforme in vitro

et al. 2021

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The most widespread and challenging aggressive malignant tumor in the brain is glioblastoma multiforme (GBM). GBM is characterized, in particular, by significant intratumor cell variability, high growth rates, and widespread invasiveness within the surrounding normal brain parenchyma. The present study aimed to examine the impact of the natural product Zerumbone, a promising sesquiterpenoid phytochemical from Zingiber zerumbet, on U-87 MG GBM cells and its underlying molecular mechanisms. At sub-lethal doses, Zerumbone exerted a concentration-and time-dependent suppression of cell migration ability utilizing scratch wound closure assay; it also inhibited GBM cells' invasion using Transwell invasion assay in a concentration-dependent fashion. The enzymatic activity of matrix metalloproteinase (MMP)-2/-9 and their protein expression has also been reduced by administration of Zerumbone. Furthermore, Zerumbone was revealed to downregulate the mRNA expression level of IL-1β and MCP-1, two genes contributing to MMPs expression. We also found that Zerumbone exerted an inhibitory effect on the expression of Akt and total p44/42 MAPK (Erk1/Erk2) against U-87 MG cells.These findings collectively provide further proof for the possible molecular signaling basis of the antimetastatic effects of Zerumbone as a promising

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“…However, patient outcomes from these treatments remain contentious. Clinical trials of immunotherapy with anti-programmed cell death 1 antibodies also did not meet clinical survival endpoints in patients with GBM (Khasraw et al, 2020;Maghrouni et al, 2021). Overactivation of the PI3K pathway occurs frequently in GBM, including in those with TMZ resistance (Sami and Karsy, 2013).…”

Section: Discussionmentioning

confidence: 99%

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

Zhang

Lin

et al. 2021

Front. Pharmacol.

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Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

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Targeting the PD-1/PD-L1 pathway in glioblastoma multiforme: Preclinical evidence and clinical interventions

Cited by 33 publications

References 149 publications

Identification of an N6-methyladenosine (m6A)-related signature associated with clinical prognosis, immune response, and chemotherapy in primary glioblastomas

Identification of an N6-methyladenosine (m6A)-related signature associated with clinical prognosis, immune response, and chemotherapy in primary glioblastomas

Zerumbone, a ginger sesquiterpene, inhibits migration, invasion, and metastatic behavior of human malignant glioblastoma multiforme in vitro

The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

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