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NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD-L1-dependent manner

ABSTRACT: This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRCTo investigate the potential of NFKB2 as a therapeutic target for colorectal cancer (CRC), we conducted a systematic analysis of the molecular mechanism and function of NFKB2 in CRC. VariousA range of experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtaingain a deeper understanding of the regulation of NFKB2 in CRC. TheOur results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasismetastases of CRC. NFKB2 played an importanta role in promoting tumor growth through CD8+ T cell exhaustion. MoreoverAdditionally, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2)STAT2, leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1)PD-L1 expression. Applying aThe application of a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 (PD-1)PD-1 blockade-based immunotherapy. In conclusion,These findings suggest that the facilitated NFKB2-STAT2/PD-L1 axis may suppresses immune surveillance in CRC and targeting NFKB2 maycould enhance the efficacy of immunotherapeutic strategies. Our resultsThis study provides novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape. However, our findings requireand further validation of these findings in a clinical trial is needed to establish NFKB2 inhibition as a therapeutic strategy for CRC patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE250065 | GEO | 2023/12/21

REPOSITORIES: GEO

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Project description:Aim: The aim of this study is to explore the impact of Pien Tze Huang (PZH) on enhancing T cell cytotoxicity by modulating colorectal cancer stem cell (CRC-CSC) markers, programmed death protein ligand-1 (PD-L1), and the transcription factor signal transducer and activator of transcription 3 (STAT3) protein expression in vivo, ex vivo, and in vitro. Methods: HCT116, HCT15, and SW480 cell lines were subjected to treatment with PZH, followed by assessment of cell viability and stemness through CCK8 and spheroid formation assays. Western blot and immunofluorescence techniques were employed to evaluate the expression levels of stem cell markers (DCLK1, CD133, CD44, MET, and LGR5), PD-L1, and STAT3 across three CRC cell lines and five patient-derived organoids (PDOs). Flow cytometry and western blot analyses were utilized to validate T cell expansion from both donors and CRC patients. CRC cells and CRC-PDOs, pre-treated with PZH, were co-cultured with expanded T cells from both donor and autologous peripheral blood mononuclear cells (PBMCs) respectively. The viability of CRC cells and PDOs was evaluated through Calcein-AM staining to measure fluorescence intensity and cell count following co-culture. In the syngeneic MC38 C57BL/6 xenograft model, tumor growth curve and body weight were monitored subsequent to treatment with PZH, anti-PD-1, and PZH combined with anti-PD-1. Immunohistochemistry was performed to assess protein levels of CD133, CD44, STAT3, PD-L1, CD8, and IL-6R in tumor tissue. Results: The effectiveness of PZH in reducing CRC cell viability and suppressing stemness markers, such as LGR5, CD44, MET, DCLK1, and CD133, is evident. PZH also displayed inhibitory effects on tumorigenesis in five CRC-PDOs, with varying sensitivity across cases (3 sensitive and 2 less sensitive). Moreover, PZH enhanced the cytotoxicity of donor T cells against CRC cells and rectified the cytotoxic deficiency or bolstered the cytotoxicity of autologous T cells against CRC-PDOs by downregulating PD-L1 and STAT3 protein expressi Conclusion: PZH enhances T cell-mediated killing effect by inhibiting CRC stem cell markers, PD-L1, and STAT3. Key Words: Pien Tze Huang, patient-derived organoid, colorectal cancer stem cells, programmed death protein ligand-1, signal transducer and activator of transcription 3

Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.

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NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD-L1-dependent manner

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