Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal

Abstract

The negative role of the activated stimulator of IFN genes (STING) has been uncovered in autoinflammatory disease and cancer. However, the role of STING in virus-related carcinogenesis is not well known. Herein, HPV(+) tongue squamous cell carcinoma (TSCC) (n=25) and HPV(-) TSCC samples (n=25) were randomly collected and were verified by in situ hybridization (ISH) and p16 immunohistochemistry (IHC) to assess the expression and activated status of STING through IHC. The results showed that the expression of STING was up-regulated during the development of TSCC. Interestingly, although the expression of STING showed no difference between HPV(+/-) TSCC samples, the activated status of STING with dark staining around the nucleus was observed in HPV(+) TSCC samples. The role of activated STING was analyzed in three cell lines by siRNA and indicated that activated STING had no impact on cell viability or apoptosis but promoted the induction of several immunosuppressive cytokines, e.g., IL-10, IDO and CCL22, which facilitated the infiltration of regulatory T cells (Tregs). Moreover, increased infiltration of Foxp3(+) Tregs along with increased expression of CCL22 was confirmed in HPV(+) TSCC samples. An inhibitor of the MAPK/AP-1 pathway (U0126) and the silencing of c-jun significantly suppressed CCL22 induction and the recruitment of Tregs by activated STING. Furthermore, down-regulated miR-27 was verified in independent fresh TSCC samples (n=50) and eight cell lines, which enhanced STING activation and led to increased CCL22 expression for Tregs recruitment in the TSCC microenvironment. Therefore, our findings provided distinct insight into the side effects of activated STING in HPV-related carcinogenesis.

Immune-related gene signature for predicting the prognosis of head and neck squamous cell carcinoma

“…ES is short for enrichment score controls immune cell trafficking in reaction to inflammatory stimuli, hence determining the metastasis of HNSCC cells in vivo [21]. CCL22, an immunosuppressive cytokine, facilitates Tregs infiltration in the HPV-related tongue squamous cell carcinoma [27]. The most significant biological processes that appear to negatively correlate with the immune risk are IFN-α responses, IFN-γ responses, IL-2/STAT5 signaling and IL-6/JAK/STAT3 signaling, all of which were associated with tumor immunity.…”

STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

“…Interestingly, STING down-regulation in the tumor microenvironment has been associated with tumor-igenesis and poor prognosis in melanoma, colorectal and gastric cancers [16–18]. .In HNSCC, STING was found to be activated in HPV + tumor specimens [19]. Other studies revealed that the HPV oncoprotein E7 inhibits STING signaling pathway by blocking its interaction with IRF3 raising a question regarding the role of STING in HNSCC [7,20], and EGFR signaling was shown to modulate phosphorylation of IRF3 and TBK1 [21].…”

miR‐193b availability is antagonized by LncRNA‐SNHG7 for FAIM2‐induced tumour progression in non‐small cell lung cancer

“…4,5 The aberrant expression of miRNA and LncRNA was found to be involved into the progression of cancer. [6][7][8][9] miR-34 and let-7 were found to be tumoursuppressive miRNAs in lung cancer, systemic nano-delivery of miR-34…”