GATA1 knockdown enhances CD8+ T cell responses and protects against immune escape in cervical squamous cell carcinoma through FGL1 downregulation

Juan Zhou; Fang Liu; Tingting Gao; Ying Yang

Just Accepted

This article has been peer reviewed and accepted for publication. It is in production and has not been edited, so may differ from the final published form.

GATA1 knockdown enhances CD8+ T cell responses and protects against immune escape in cervical squamous cell carcinoma through FGL1 downregulation

Juan Zhou, Fang Liu , Tingting Gao, Ying Yang

Abstract

Context: Immune escape is a hallmark of cancers, which affects the efficacy of immunotherapy. Background: 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. Methods: 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 in Caski cells, Caski cells were co-cultured with CD8+ T cells, followed by assessments for the sensitivity of Caski cells to CD8+ T cells, the secretion of perforin, GzmB, IFN-γ, and TNF-α, CD8+ T cell proliferation and apoptosis. The binding of GATA1 to the FGL1 promoter was validated through luciferase and ChIP assays. GATA1-knockdown Caski cells were inoculated into immunocompetent mice in combination with or without CD8α mAb to ascertain the impacts of GATA1 on tumor growth and immune escape in CESC in vivo. Key results: Knockdown of either FGL1 or GATA1 markedly enhanced the sensitivity of Caski cells to CD8+ T cell-mediated cytotoxicity, the secretion of perforin, GzmB, IFN-γ, and TNF-α, and CD8+ T cell proliferation but greatly decreased CD8+ T cell apoptosis. Conclusions: 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. Implications: Altogether, GATA1 knockdown facilitates CD8+ T cell responses and suppresses immune escape in CESC by downregulating FGL1.

RD24042 Accepted 15 August 2024