Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity

Punt, Simone; Malu, Shruti; McKenzie, Jodi A.; Manrique, Soraya Zorro; Doorduijn, Elien M.; Mbofung, Rina M.; Williams, Leila J.; Silverman, Deborah A.; Ashkin, Emily L.; Dominguez, Ana Lucía; Wang, Zhe; Chen, Jie Qing; Maiti, Sourindra N.; Tieu, Trang N.; Liu, Chengwen; Xu, Chunyu; Forget, Marie-Andrée; Haymaker, Cara; Khalili, Jahan S.; Satani, Nikunj; Müller, Florian; Cooper, Laurence J.N.; Overwijk, Willem W.; Amaria, Rodabe N.; Bernatchez, Chantale; Heffernan, Timothy P.; Peng, Weiyi; Roszik, Jason; Hwu, Patrick

doi:10.1007/s00262-020-02748-9

Cited by 21 publications

(18 citation statements)

References 45 publications

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“…In contrast, CD4+ T cells secrete a variety of cytokines with direct effector functions and activate other immune cells such as B cells and CD8 T cells [38].In the present study, we also observed that AURKA inhibited the immune-infiltrating levels of anti-tumor immune cells (DC, B cells, CD4+ T cells, and CD8+ T cells) in the TME, while increasing the infiltration level of tumor immune escape-promoting cells (MDOS, ). Our findings are consistent with that of previous reports [31,39,40]suggesting that AURKA can inhibit the increased level of antitumor immune cell infiltration in the TME. We postulate that the formation of the immunosuppressive microenvironment is promoted for the following.…”

Section: Mutations In Genes In Normal Cells Promote the Progression O...supporting

confidence: 94%

“…Recent studies have demonstrated that AURKA, which is highly expressed in SKCM, inhibits effector T cell-mediated cytotoxicity [31]. At the same time, the functional annotation results indicated that AURKA influences the TME, therefore, we further investigated the correlation between AURKA and TME.…”

Section: Aurka Reshapes the Tumor Immunosuppressive Microenvironmentmentioning

confidence: 92%

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AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia

Long

Zhang

2022

J Cancer Res Clin Oncol

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Background: AURKA, Aurora kinase A encoding gene, is an important signaling hub gene for mitosis. In recent years, AURKA has been implicated in the occurrence and development of several cancers. However, its relationship with the tumor microenvironment in skin cutaneous melanoma (SKCM) and the molecular mechanisms underlying its effects are still unclear. Method：We adopted a variety of bioinformatics methods to comprehensively analyze the potential carcinogenesis of AURKA in SKCM, and constructed a prognostic nomogram model. We also dentified an inhibitor targeting AURKA and verified its therapeutic effects against SKCM using the molecular docking technology. Results:We found that abnormally high expression of AURKA was responsible for driving the occurrence and development of SKCM, and affected various pathological factors in SKCM. In addition, AURKA was established as an independent marker of poor SKCM prognosis. We also characterized the potential mechanisms by which AURKA manifests its effects in SKCM and found that AURKA inhibits the infiltration of CD8+ T cells and promotes hypoxia by activating the TGF-β signaling pathway. At the same time, the high AURKA expression group had higher tumor stemness index and promoted cell proliferation and metastasis. Finally, the small molecule compound ZNC97018978 targeting AURKA screened by molecular docking technology can inhibit the proliferation, invasion and metastasis of SKCM. The possible mechanism is that ZNC97018978 induces apoptosis by arresting the cell cycle, thereby inhibiting cell proliferation. Conclusion:AURKA is the core hub gene driving the occurrence and development of SKCM, and its expression is regulated by epigenetic modifications. AURKA can regulate the infiltration level of various immune cells in the tumor microenvironment, reshape the immunosuppressive tumor microenvironment, and apoptosis, and hypoxia. Thus, it is a prognostic biomarker and potential therapeutic target in SKCM. ZNC97018978 is an effective and safe inhibitor of AURKA in vitro; its safety and effectiveness in vivo as a potential treatment for cutaneous melanoma should be further determined.

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Section: Mutations In Genes In Normal Cells Promote the Progression O...supporting

confidence: 94%

Section: Aurka Reshapes the Tumor Immunosuppressive Microenvironmentmentioning

confidence: 92%

AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia

Long

Zhang

2022

J Cancer Res Clin Oncol

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“…Many previous studies have found that the expression level and activity of these two kinases are upregulated in different tumors (56)(57)(58). Furthermore, Punt et al reported that the transcriptome and protein levels of Aurora kinase have significant negative correlations with immunocyte infiltration, the immunotherapeutic response and survival in patients with melanoma, and Aurora kinases were identified to be involved in the resistance of melanoma cells to T-cell-mediated cytotoxicity (59). In our study, AURKA and AURKB were significantly negatively correlated with mast cell infiltration and KITLG expression levels in the analysis of multiple databases.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance and Regulatory Network of Mast Cells in Early-Stage Lung Adenocarcinoma

Wang

Luo

Duan

et al. 2021

Preprint

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Background The role and upstream regulation of mast cells (a crucial constituent of the tumor immune microenvironment) in early-stage lung adenocarcinoma (LUAD) remains unclear. Methods Using CIBERSORT, we analyzed the expression profile downloaded from the NCBI Gene Expression Omnibus (GEO) database. Next, using weighted gene coexpression network analysis (WGCNA) and enrichment analysis, we identified upstream regulators of mast cells. Finally, we verified their relevance using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Results Among patients with early-stage LUAD, those with high mast cell infiltration levels had a better prognosis, and mast cell infiltration levels were closely associated with the mutation status of TP53, STK11 and EGFR. CAMK2D, AURKA, AURKB, PLK1 and EZH2 showed strong correlations with mast cell infiltration and a key growth factor of mast cells (KITLG), and these 5 regulators were closely correlated with the survival of patients with early-stage lung adenocarcinoma. Conclusion Mast cells play a protective role in patients with early-stage LUAD. We speculate that CAMK2D, AURKA, AURKB, PLK1 and EZH2 promote or inhibit the infiltration of mast cells in early-stage lung adenocarcinoma tissues by regulating KITLG, likely serving as novel targets in immunotherapy for LUAD.

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“…This substantiates the anti-proliferative effect of CM-272 on MO4 cells. Notably, p21 upregulation has been shown to sensitize melanoma cells to T-cell cytotoxicity ( 56 ). Accordingly, we found improved recognition of CM-272-treated tumors by T cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma

et al. 2022

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Immunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in the preclinical B16-OVA melanoma model. Making use of tumor transcriptomic and functional analyses, methylation-targeted epigenetic reprogramming was shown to induce tumor cell cycle arrest and apoptosis in vitro coinciding with transient tumor growth delay and an IFN-I response in immune-competent mice. In consideration of a potential impact on immune cells, the drug was shown not to interfere with dendritic cell maturation or T-cell activation in vitro. Notably, the drug promoted dendritic cell and, to a lesser extent, T-cell infiltration in vivo, yet failed to sensitize tumor cells to programmed cell death-1 inhibition. Instead, it increased therapeutic efficacy of TCR-redirected T cell and dendritic cell vaccination, jointly increasing overall survival of B16-OVA tumor-bearing mice. The reported data confirm the prospect of methylation-targeted epigenetic reprogramming in melanoma and sustain dual G9a and DNMT inhibition as a strategy to tip the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma.

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Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity

Cited by 21 publications

References 45 publications

AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia

AURKA is a prognostic potential therapeutic target in skin cutaneous melanoma modulating the tumor microenvironment, apoptosis, and hypoxia

Clinical Significance and Regulatory Network of Mast Cells in Early-Stage Lung Adenocarcinoma

Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma

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