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Published on: February 9, 2024
GATA1 knockdown enhances CD8+ T cell responses and protects against immune escape in cervical squamous cell carcinoma
Juan Zhou1, Fang Liu2, Tingting Gao3
1Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Military Medical University, 1 Xinsi Road, Baqiao District, Xi'an, 710038, China.
Abstract:
Immune escape is a hallmark of cancers, which affects the efficacy of immunotherapy. Herein, this study analyzed the significance of GATA1/FGL1 in the immune escape of cervical squamous cell carcinoma (CESC) to deepen the understanding of immune escape-associated molecular mechanisms. In silico analysis predicted the correlations of FGL1 with CESC prognosis and CD8+ T cell infiltration as well as the relation between FGL1 and GATA1. After FGL1 and/or GATA1 gain- and loss-of-function, CC cells were co-cultured with CD8+ T cells. The sensitivity of CC cells to CD8+ T cells was assessed, as well as the secretion of perforin, GzmB, IFN-γ, and TNF-α. Also, CD8+ T cell proliferation and apoptosis were measured. The binding of GATA1 to the FGL1 promoter was validated through luciferase and ChIP assays. GATA1-knockdown U14 cells were transplanted into immunocompetent C57BL/6 mice in combination with or without CD8α mAb to ascertain the impacts of GATA1 on tumor growth and immune escape in CESC in vivo. Knockdown of either FGL1 or GATA1 markedly enhanced the sensitivity of CC cells to CD8+ T cell‑mediated cytotoxicity and increased the secretion of perforin, GzmB, IFN‑γ, and TNF‑α. It also promoted CD8+ T cell proliferation while reducing their apoptosis. These effects of GATA1 knockdown were partially negated by FGL1. In vivo, GATA1 knockdown prominently diminished the tumor growth and increased the infiltration and cytotoxic effects of CD8+ T cells. Collectively, GATA1 knockdown facilitates CD8+ T cell responses and suppresses immune escape in CESC by downregulating FGL1.
Insights
GATA1/FGL1 signaling promotes immune escape in cervical squamous cell carcinoma (CESC). Downregulating GATA1 enhances CD8+ T cell responses, suppressing tumor growth and improving immunotherapy efficacy in CESC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune escape is a critical challenge in cancer immunotherapy.
- Understanding molecular mechanisms of immune escape in cervical squamous cell carcinoma (CESC) is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of GATA1 and FGL1 in the immune escape of CESC.
- To elucidate the molecular mechanisms by which GATA1/FGL1 signaling influences anti-tumor immunity.
Main Methods:
- In silico analysis to predict correlations between FGL1, prognosis, and CD8+ T cell infiltration in CESC.
- In vitro co-culture assays with cervical cancer cells and CD8+ T cells to assess cytotoxicity, cytokine secretion, and T cell responses.
- In vivo studies using a mouse model of CESC to evaluate the impact of GATA1 knockdown on tumor growth and immune cell infiltration.
Main Results:
- Knockdown of FGL1 or GATA1 significantly enhanced CD8+ T cell-mediated cytotoxicity against CESC cells.
- GATA1 knockdown increased the secretion of cytotoxic molecules (perforin, GzmB, IFN-γ, TNF-α) and promoted CD8+ T cell proliferation while reducing apoptosis.
- In vivo, GATA1 knockdown suppressed tumor growth and augmented CD8+ T cell infiltration and cytotoxic activity.
Conclusions:
- GATA1 knockdown suppresses immune escape in CESC by downregulating FGL1, thereby facilitating CD8+ T cell responses.
- Targeting the GATA1/FGL1 axis represents a potential therapeutic strategy to enhance immunotherapy efficacy in cervical cancer.
