EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Pan, Yihui; Shu, Guannan; Fu, Liangmin; Huang, Kaijun; Zhou, Xinwei; Gui, Chengpeng; Liu, Huashan; Jin, Xiaohan; Chen, Minyu; Li, Pengju; Cen, Junjie; Lü, Jun; Chen, Zhenhua; Xu, Quanhui; Wang, Yinghan; Liang, Hui; Wang, Zhu; Deng, Qing; Chen, Wei; Luo, Junhang; Yang, Jiefeng; Zhang, Jiaxing; Wei, Jinhuan

doi:10.1002/advs.202206792

Cited by 16 publications

(7 citation statements)

References 57 publications

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“…However, the efficacy of these therapies remains limited, with persistent immune suppression and resistance observed in the tumor microenvironment (TME). Therefore, it is imperative to identify new therapeutic targets to enhance the efficacy of immunotherapeutic agents for RCC 40 – 42 . Notably, targeting DHODH is a potential strategy for anti-ccRCC immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

Wang,

Li,

Lin

et al. 2024

Sci Rep

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Clear cell renal cell carcinoma (ccRCC) is a malignant tumor of the urinary system. To explore the potential mechanisms of DHODH in ccRCC, we analyzed its molecular characteristics using public databases. TCGA pan-cancer dataset was used to analyze DHODH expression in different cancer types and TCGA ccRCC dataset was used to assess differential expression, prognosis correlation, immune infiltration, single-gene, and functional enrichment due to DHODH. The GSCALite and CellMiner databases were employed to explore drugs and perform molecular docking analysis with DHODH. Protein–protein interaction networks and ceRNA regulatory networks of DHODH were constructed using multiple databases. The effect of DHODH on ccRCC was confirmed in vitro. DHODH was highly expressed in ccRCC. Immune infiltration analysis revealed that DHODH may be involved in regulating the infiltration of immunosuppressive cells such as Tregs. Notably, DHODH influenced ccRCC progression by forming regulatory networks with molecules, such as hsa-miR-26b-5p and UMPS and significantly enhanced the malignant characteristics of ccRCC cells. Several drugs, such as lapatinib, silmitasertib, itraconazole, and dasatinib, were sensitive to DHODH expression and exhibited strong molecular binding with it. Thus, DHODH may promote ccRCC progression and is a candidate effective therapeutic target for ccRCC.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

Wang,

Li,

Lin

et al. 2024

Sci Rep

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“…In addition, CTSF expression was negatively correlated with the expression of several immunoinhibitors (including CTLA4, TIGIT, CD96, LAG3, CD274, BTLA, PDCD1LG2 and PDCD1), immunostimulators (including ICOS, CD80, TNFRSF9, IL2RA, CD28, LTA, TNFSF13B, MICB, TNFSF4, TNFSF14, KLRK1 and CD86), and MHC molecules (including TAP1 and TAP2) in ccRCC. Published work have shown that high lymphocyte infiltration and immunosuppression characterized the immune microenvironment in ccRCC and contributed to cancer development 28 , 29 . Infiltration of CD8 + T cells within the tumor microenvironment (TME) may be associated with a poor prognostic marker and may predict the response to immune checkpoint blockade (ICB) in ccRCC 28 .…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of cathepsin F predicts poor prognosis in patients with clear cell renal cell carcinoma

Zhou,

Chen,

Huang

et al. 2024

Sci Rep

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Abnormalities in the extracellular matrix (ECM) play important roles in the regulation and progression of clear cell renal cell carcinoma (ccRCC). The cysteine cathepsin is one of the major proteases involved in ECM remodeling and has been shown to be aberrantly expressed in multiple cancer types. However, the clinical significance and biological function of distinct cysteine cathepsins in ccRCC remain poorly understood. In this study, several bioinformatics databases, including UALCAN, TIMER, GEPIA and the Human Protein Atlas datasets, were used to analyze the expression and prognostic value of different cysteine cathepsin family members in ccRCC. We found that the expression level of CTSF was downregulated in tumor tissues and closely related to the poor survival of ccRCC patients. Further in vitro experiments suggested that CTSF overexpression suppressed the proliferation and migration of ccRCC cells. Moreover, the expression of CTSF was shown to be associated with several immune-infiltrating cells and immunomodulators in ccRCC. These results indicated that CTSF might be a promising diagnostic and prognostic marker in ccRCC.

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“…Furthermore, IFN-γ signalling can be effectively maintained within tumours through EH domain-binding protein 1-like protein 1 (EHBP1L1) shielding JAK1 from proteasomal degradation. This mechanism promoted PD-L1 expression in a mouse model of renal cell carcinoma (RCC) and EHBP1L1 inhibition resulted in increased CTL activity and improved response to ICBT [ 73 ].…”

Section: Negative-feedback Regulators Of Ifn-γ Signallingmentioning

confidence: 99%

The role of IFN-γ-signalling in response to immune checkpoint blockade therapy

Wong

Huang

Hurlstone

2023

Essays in Biochemistry

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Treatment with immune checkpoint inhibitors, widely known as immune checkpoint blockade therapy (ICBT), is now the fourth pillar in cancer treatment, offering the chance of durable remission for patients with advanced disease. However, ICBT fails to induce objective responses in most cancer patients with still others progressing after an initial response. It is necessary, therefore, to elucidate the primary and acquired resistance mechanisms to ICBT to improve its efficacy. Here, we highlight the paradoxical role of the cytokine interferon-γ (IFN-γ) in ICBT response: on the one hand induction of IFN-γ signalling in the tumour microenvironment correlates with good ICBT response as it drives the cellular immune responses required for tumour destruction; nonetheless, IFN-γ signalling is implicated in ICBT acquired resistance. We address the negative feedback and immunoregulatory effects of IFN-γ signalling that promote immune evasion and resistance to ICBT and discuss how these can be targeted pharmacologically to restore sensitivity or circumvent resistance.

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EHBP1L1 Drives Immune Evasion in Renal Cell Carcinoma through Binding and Stabilizing JAK1

Cited by 16 publications

References 57 publications

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

Bioinformatics analysis and experimental verification of the cancer-promoting effect of DHODH in clear cell renal cell carcinoma

Reduced expression of cathepsin F predicts poor prognosis in patients with clear cell renal cell carcinoma

The role of IFN-γ-signalling in response to immune checkpoint blockade therapy

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