Blocking PD1/PDL1 Interactions Together with MLN4924 Therapy is a Potential Strategy for Glioma Treatment

Filippova, Natalia; Yang, Xiuhua; An, Zixiao; Nabors, Louis B.; Pereboeva, Larisa

doi:10.4172/1948-5956.1000543

Cited by 27 publications

(24 citation statements)

References 44 publications

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“…48,49 However, single blockade of immune checkpoint molecules (such as PD1 and PD-L1) cannot effectively eliminate cancer cells. 42,50 A combination with cancer immunotherapy might enhance the anti-tumor effect. 42 The results also suggested that the combination therapy could reverse tumor-induced immunosuppression and enhance anti-tumor immunity, as evidenced by the increase in tumor-infiltrating effector CD4 + T cells and CD8 + T cells, decrease in Treg cells and MDSCs, and the longer survival time of the tumor-bearing mice.…”

Section: Discussionmentioning

confidence: 99%

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Zhang

et al. 2020

OncoImmunology

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In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2 D4) was found to enhance IFN-γ-producing-CD8 + T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2 D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2 D4 and antitumor immunity, as evidenced by the reversal of tumor-infiltrating CD8 + T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.

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Section: Discussionmentioning

confidence: 99%

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Zhang

et al. 2020

OncoImmunology

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“…Differential expression of 7 established immune checkpoint genes in the low and high-risk groups was analyzed. These are, T cell immunoglobulin domain and mucin domain 3 (TIM3), programmed cell death 1 (PD1), PD1 interacts with programmed death ligand 1 (PDL1), cytotoxic T lymphocyte antigen 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), long non-coding RNA MIR 155 host gene (MIR155HG), and CD48 [20][21][22][23][24] . This analysis evaluated the correlation between risk score and expression of the checkpoint genes.…”

Section: Analysis Of Correlation Between Risk Score and Expression Ofmentioning

confidence: 99%

A 1p/19q Codeletion-Associated Immune Signature for Predicting Lower Grade Glioma Prognosis

Liu

et al. 2020

Cell Mol Neurobiol

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Background: Lower grade gliomas (LGGs) with codeletion of chromosomal arms 1p and 19q (1p/19 codeletion) has a favorable outcome. However, its overall survival (OS) varies. Here, we established an immune signature associated with 1p/19q codeletion for accurate prediction of prognosis of LGGs. Methods: We extracted RNA sequencing and corresponding clinical data of LGGs from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). The CGGA and TCGA databases were dichotomized into training group and testing group. The immune-related differentially expressed genes (DEGs) associated with 1p/19q codeletion were screened using Cox proportional hazards regression analyses. A prognostic signature was established using dataset from CGGA and tested in TCGA datasets. Subsequently, we explored the correlation between the prognostic signature and immune response. Results: Thirteen immune genes associated with 1p/19q codeletion were identi ed and used to construct a prognostic signature. The 1-, 3-, 5-year survival rates of the low-risk group were approximately 97%, 89%, and 79%, while those of the high-risk group were 81%, 50% and 34%, respectively in the training group. The nomogram which comprised of age, world health organization (WHO) grade, primary or recurrent types, 1p/19q codeletion status and risk score provided accurate prediction for the survival rate of glioma. DEGs that were highly expressed in the high-risk group clustered with many immune-related pathways. Immune checkpoints including T cell immunoglobulin domain and mucin domain 3 (TIM3), programmed cell death 1 (PD1), PD1 interacting with programmed death ligand 1 (PDL1), cytotoxic T lymphocyte antigen 4 (CTLA4), T cell immunoreceptor with Ig and ITIM domains (TIGIT), long non-coding RNA MIR 155 host gene (MIR155HG), and CD48 were correlated with the risk score. VAV3 and TNFRFSF11B were found to be candidate immune checkpoints. Conclusion: The 1p/19q codeletion-associated immune signature provides accurate prediction of OS. VAV3 and TNFRFSF11B are novel immune checkpoints.

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“…MLN4924, a small molecular inhibitor of NAE [17,18], has been developed as a first-in-class neddylation inhibitor. Intensive studies reported that MLN4924 induced the accumulation of tumor-suppressive CRLs substrates to suppress cancer cell growth and metastasis both in vitro and in vivo , owing to the inhibition of Cullin neddylation and CRLs activation [[19], [20], [21], [22], [23], [24], [25], [26]]. Due to its high efficiency and well-tolerated toxicity in preclinical trials, MLN4924 has advanced into clinical trials for human hematological malignancies and solid tumors [[27], [28], [29], [30]].…”

Section: Introductionmentioning

confidence: 99%

Validation of NEDD8-conjugating enzyme UBC12 as a new therapeutic target in lung cancer

Kang

Zhang

et al. 2019

EBioMedicine

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Background The neddylation pathway is overactivated in human cancers. Inhibition of neddylation pathway has emerged as an attractive anticancer strategy. The mechanisms underlying neddylation overactivation in cancer remain elusive. MLN4924/Pevonedistat, a first-in-class NEDD8-activating enzyme (NAE, E1) inhibitor, exerts significant anti-tumor effects, but its mutagenic resistance remains unresolved. Methods The expression of NEDD8-conjugating enzyme UBC12/UBE2M (E2) and NEDD8 were estimated by bioinformatics analysis and western blot in human lung cancer cell lines. The malignant phenotypes of lung cancer cells were evaluated both in vitro and in vivo upon UBC12 knockdown. Cell-cycle arrest was evaluated by quantitative proteomic analysis and propidium iodide stain and fluorescence - activated cell sorting (FACS). The growth of MLN4924 - resistant H1299 cells was also evaluated upon UBC12 knockdown. Findings The mRNA level of UBC12 in lung cancer tissues was much higher than that in normal lung tissues, increased with disease deterioration, and positively correlated with NEDD8 expression. Moreover, the overexpression of UBC12 significantly enhanced protein neddylation modification whereas the downregulation of UBC12 reduced neddylation modification of target proteins. Functionally, neddylation inactivation by UBC12 knockdown suppressed the malignant phenotypes of lung cancer cells both in vitro and in vivo . The quantitative proteomic analysis and cell cycle profiling showed that UBC12 knockdown disturbed cell cycle progression by triggering G 2 phase cell-cycle arrest. Further mechanistical studies revealed that UBC12 knockdown inhibited Cullin neddylation, led to the inactivation of CRL E3 ligases and induced the accumulation of tumor-suppressive CRL substrates (p21, p27 and Wee1) to induce cell cycle arrest and suppress the malignant phenotypes of lung cancer cells. Finally, UBC12 knockdown effectively inhibited the growth of MLN4924-resistant lung cancer cells. Interpretation These findings highlight a crucial role of UBC12 in fine-tuned regulation of neddylation activation status and validate UBC12 as an attractive alternative anticancer target against neddylation pathway. Fund Chinese Minister of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81401893, 81625018, 81820108022, 81772470, 81572340 and 81602072), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), Program of Shanghai Academic/Technology Research Leader (18XD1403800), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001). The funders had no role in study design, data collection, data analysis, interpretation, writing of the...

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Blocking PD1/PDL1 Interactions Together with MLN4924 Therapy is a Potential Strategy for Glioma Treatment

Cited by 27 publications

References 44 publications

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

A 1p/19q Codeletion-Associated Immune Signature for Predicting Lower Grade Glioma Prognosis

Validation of NEDD8-conjugating enzyme UBC12 as a new therapeutic target in lung cancer

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