Dichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC

Bickett, Thomas; Knitz, Michael; Piper, Miles; Oweida, Ayman; Gadwa, Jacob; Darragh, Laurel B.; Nguyen, Diemmy; Bhuvane, Shiv; Phan, Andy V.; Court, Benjamin Van; Corbo, Sophia; Pham, Tiffany; Dent, Alexander L.; Lenz, Laurel; Karam, Sana D.

doi:10.1016/j.ymthe.2021.11.011

Cited by 6 publications

(5 citation statements)

References 53 publications

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“…It has been suggested that these high PD-L1 expression scores are simply a reflection of strong underlying IFN signaling, since STAT1 upregulates PD-L1 in addition to APM components [ 19 ]. However, PD-L1 expression can also be driven by STAT3 [ 19 ], which functions as an oncogene and is associated with immunosuppressive myeloid cells [ 20 – 22 ]. To determine to what degree PD-L1 expression depends on STAT1, we examined inducible PD-L1 expression upon treatment of our cell lines with IFN-γ and/or cisplatin, which also activates STAT1 and promotes PD-L1 expression [ 8 , 10 ].…”

Section: Resultsmentioning

confidence: 99%

Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional STAT1 and p53

Kinney,

Gunti,

Kansal

et al. 2024

Cancer Immunol Immunother

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The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role. In the current study, we aimed to investigate the extent to which STAT1 and p53 individually regulate APM component expression in HNSCC cells. We found that in cells lacking functional p53, APM expression could still be induced by interferon-gamma or DNA-damaging chemotherapy (cisplatin) as long as STAT1 expression remained intact; when both transcription factors were knocked down, APM component expression was abolished. When we bypassed these deficient pathways by rescuing the expression of NLRC5, APM expression was also restored. These results suggest that dual loss of functional STAT1 and p53 may render HNSCC cells incapable of processing and presenting antigens, but rescue of downstream NLRC5 expression may be an attractive strategy for restoring sensitivity to T cell-based immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional STAT1 and p53

Kinney,

Gunti,

Kansal

et al. 2024

Cancer Immunol Immunother

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“… 26 , 85 The STAT3/Foxp3 axis suppression in Tregs from head and neck squamous cell carcinoma contribute to Treg reprogramming and activation of antigen‐presenting cells, ultimately improved head and neck tumor growth delay. 86 Moreover, inhibiting the IL‐6‐STAT3/Foxp3 cascade showed immune‐related antitumor effect in hepatocellular carcinoma, wherein IL‐6‐STAT3 signaling inactivation suppressed Foxp3 expression in Tregs. 87 However, in colorectal cancer patients inflammatory infiltrate response, the the upregulate of STAT was negatively associated with Foxp3+ T lymphocytes and potential to relieve local and systemic inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…In terms of this, STAT3 and Foxp3 interaction site was exist in the promoter of tumor induced Tregs and associated with several tumors progression 26,85 . The STAT3/Foxp3 axis suppression in Tregs from head and neck squamous cell carcinoma contribute to Treg reprogramming and activation of antigen‐presenting cells, ultimately improved head and neck tumor growth delay 86 . Moreover, inhibiting the IL‐6‐STAT3/Foxp3 cascade showed immune‐related antitumor effect in hepatocellular carcinoma, wherein IL‐6‐STAT3 signaling inactivation suppressed Foxp3 expression in Tregs 87 .…”

Section: Discussionmentioning

confidence: 99%

Investigation on the regulatory T cells signature and relevant Foxp3/STAT3 axis in esophageal cancer

Yang

Zhao

Wang³

et al. 2022

Cancer Medicine

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Background: Regulatory T cells (Tregs) have an important role in accelerating the immunosuppression of tumor. Tregs regulation is a hopeful strategy to improve the dismal prognosis of Esophageal cancer (EC), while its mechanisms have not yet been fully clarified. Methods: To characterize the role of Tregs in EC, we comprehensively explored its prognostic value, clinical pathology partnership, related biological functions and potential mechanisms at transcriptome level. Through the integrated analysis of GEO and TCGA datasets, we comprehensively evaluated the Tregs infiltration patterns in EC patients. The correlation between Tregs infiltration and genomic characteristics, as well as biological functions were analyzed by a variety of computational algorithms. Results:We observed that Tregs were significantly upregulated in EC and involved in various immune processes. According to TCGA and GEO transcriptional classification schemes, Tregs specific genes were observed to be highly expressed in tumor samples, as well as were closely associated with poor prognosis and worse clinical outcomes. In addition, EC patients can be stratified into high-risk and low-risk immune subgroups according to Tregs/macrophages infiltration level, and the results showed significant differences in tumor development, biological processes and probe gene expression pattern. The multi-variate analysis revealed that the interaction between STAT3 and Foxp3 was a potential prognostic signature of Tregs in EC, especially the modulation effect of STAT3 on Foxp3 expression, which has not been well studied in EC. We also identified that STAT3 and Foxp3 expression presented a high accuracy in predicting Tregs infiltration level in EC patients (AUC: 0.817; 95% CI: 0.756-0.878). Conclusions: Our results revealed that Tregs have the potential to predict prognosis and tumor deterioration in EC patients. A comprehensive landscape of Tregs regulation mechanisms will help us interpret the immunosuppression of tumor microenvironment (TME) and novel strategies for EC immunotherapy.

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“…Aberrant activation of STAT3 is commonly observed in 70% of cancer types and is correlated with unfavorable prognosis in patients. Therefore, targeting STAT3 represents a potential therapeutic strategy for HNSCC [ 76 , 77 ]. Furthermore, the precise mechanism by which EZH2 and STAT3 interact remains unclear; nevertheless, EZH2 has been found to facilitate the oncogenic function of STAT3 by demethylating K49 [ 78 ].…”

Section: Ezh2/prc2 Participates In the Epigenetic Regulation Of Hnsccmentioning

confidence: 99%

Polycomb repressive complex 2 and its core component EZH2: potential targeted therapeutic strategies for head and neck squamous cell carcinoma

Cheng,

Song,

Fang

et al. 2024

Clin Epigenet

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The polycomb group (PcG) comprises a set of proteins that exert epigenetic regulatory effects and play crucial roles in diverse biological processes, ranging from pluripotency and development to carcinogenesis. Among these proteins, enhancer of zeste homolog 2 (EZH2) stands out as a catalytic component of polycomb repressive complex 2 (PRC2), which plays a role in regulating the expression of homologous (Hox) genes and initial stages of x chromosome inactivation. In numerous human cancers, including head and neck squamous cell carcinoma (HNSCC), EZH2 is frequently overexpressed or activated and has been identified as a negative prognostic factor. Notably, EZH2 emerges as a significant gene involved in regulating the STAT3/HOTAIR axis, influencing HNSCC proliferation, differentiation, and promoting metastasis by modulating related oncogenes in oral cancer. Currently, various small molecule compounds have been developed as inhibitors specifically targeting EZH2 and have gained approval for treating refractory tumors. In this review, we delve into the epigenetic regulation mediated by EZH2/PRC2 in HNSCC, with a specific focus on exploring the potential roles and mechanisms of EZH2, its crucial contribution to targeted drug therapy, and its association with cancer markers and epithelial–mesenchymal transition. Furthermore, we aim to unravel its potential as a therapeutic strategy for oral squamous cell carcinoma.

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Dichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC

Cited by 6 publications

References 53 publications

Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional STAT1 and p53

Rescue of NLRC5 expression restores antigen processing machinery in head and neck cancer cells lacking functional STAT1 and p53

Investigation on the regulatory T cells signature and relevant Foxp3/STAT3 axis in esophageal cancer

Polycomb repressive complex 2 and its core component EZH2: potential targeted therapeutic strategies for head and neck squamous cell carcinoma

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