DFNA5 regulates immune cells infiltration and exhaustion

Abstract

Background DFNA5 (GSDME) belongs to Gasdermin familily that is involved in a variety of cancers and triggers cell pyroptosis after chemical treatment. However, the relationship in DFNA5 between prognosis and immune cells in diverse cancers has been receiving little attention. Tumor immune cells infiltration and exhaustion may associate with patients prognosis. The roles of DFNA5 in tumor immune cells infiltration and exhaustion have not been clarified. Methods The expression level of DFNA5 was determined by the Tumour Immune Estimation Resource and the Oncomine database. Then the impacts of DFNA5 in prognosis were assessed by Kaplan–Meier plotter and ULACAN. The correlations between DFNA5 and tumour-infiltrating lymphocytes were explored by TIMER. In addition, the relationships in the expression levels of DFNA5 and typical genes combination of tumour-infiltrating lymphocytes were analysed by GEPIA and TIMER. In this study, we screened the chemokine and immune related proteins interacted with DFNA5 using TurboID system to explore the instantaneous or weak interactions. Results DFNA5 significantly influences the prognosis in different cancers according to The Cancer Genome Atlas (TCGA). The expression levels of DFNA5 showed positive correlations to the infiltration of macrophages, CD8 + T cells, CD4 + T cells in liver hepatocellular carcinoma (LIHC), colon adenocarcinoma (COAD), and lung adenocarcinoma (LUAD). DFNA5 expression displayed obvious correlations with multiple lymphocytes gene makers in COAD, LIHC and LUAD. DFNA5 expression has effects on the prognosis of liver hepatocellular carcinoma and LUAD. DFNA5 upregulated the expression levels of PDCD1 and CD274 in a dose-dependent manner. Chemokine and immune related proteins interact with DFNA5. Conclusions These results indicate that DFNA5 is related to patient prognosis and immune cells, consisting of macrophages, CD4 + T cells, and CD8 + T cells, in diverse cancers. In addition, DFNA5 expression might contribute to the regulation of T cell exhaustion, tumour-associated macrophages (TAMs), and Tregs in COAD, LIHC and LUAD. DFNA5 may regulate immune infiltration via EIF2AK2. IFNGR1 was related to the functions of PD-L1 expression and PD-1 checkpoint pathway. These results indicate that DFNA5 levels may be act as a prognostic factor and predict the degrees of immune cells infiltration in LIHC and LUAD.

Degradation of Hexokinase 2 Blocks Glycolysis and Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death for Breast Cancer Therapy

“…In addition, it has been reported that GSDME can regulate the expression of PD-L1 . Similarly, after incubating with C-02 , we observed that C-02 could remarkably diminish PD-L1 in 4T1 cells (Figure H).…”

“…In addition, it has been reported that GSDME can regulate the expression of PD-L1. 52 Similarly, after incubating with C-02, we observed that C-02 could remarkably diminish PD-L1 When compared to the control group, cells treated with C-02 had 4560 differentially expressed genes, including 1964 downregulated genes and 2596 upregulated genes (Figure 5A,B). Subsequently, GO analysis suggested that the differential genes following C-02 treatment were enriched in the proteasome activation complex and the ubiquitin-like protein ligase binding pathway, which verified C-02 stimulated HK2 protein degradation via the ubiquitin-mediated proteasome system.…”

Calreticulin regulates the expression of MMP14 and ADAR1 through EIF2AK2 signaling to promote the proliferation and progression of malignant melanoma cells

“…The results of the present study preliminarily suggest that the knockdown of CALR significantly reduced EIF2AK2 phosphorylation, which may be related to the regulation of tumor immunity. Because in cancer studies, DFNA5 of the Gasdermin family can regulate immune infiltration through EIF2AK2 [44]. All these results reflected that EIF2AK2 played a key role in regulating tumor progression.…”

The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles

“…Increasing evidence implicates the potential connection between anti-PD-1 treatment and GSDME-mediated pyroptotic cell death in tumors [ 168 ]. Hu et al reported that GSDME expression could regulate polarity alterations in TAMs, Tregs, and T cell exhaustion [ 169 ]. GSDME might modulate immune infiltration through EIF2AK2 and augment the anti-tumor effect of anti-PD-1 therapy [ 169 ].…”

“…Hu et al reported that GSDME expression could regulate polarity alterations in TAMs, Tregs, and T cell exhaustion [ 169 ]. GSDME might modulate immune infiltration through EIF2AK2 and augment the anti-tumor effect of anti-PD-1 therapy [ 169 ]. This study indicates that GSDME may be used as a predictive indicator of immune cell infiltration in various malignancies, including liver and lung cancers [ 169 ].…”