Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Given its rising global incidence, poor prognosis, high recurrence, and metastatic potential, there is an urgent need to investigate the underlying mechanisms driving tumorigenesis and progression to develop novel treatment strategies.

Although cancer immunotherapy, especially immune checkpoint blockade (ICB) therapy, shows some promise, its effectiveness in HNSCC is limited by the tumor’s immunosuppressive microenvironment. Increased levels of regulatory T (Treg) cells, which are key immunosuppressive cells in the tumor microenvironment, as well as an increased Treg/CD8+ T cell ratio and high levels of Bcl6 in Treg cells, correlate with poorer clinical outcomes and metastasis in various cancers. However, the specific role of Bcl6 in HNSCC remains unclear.

A recent study published in the Genes & Diseases journal by a group of researchers from Chongqing Medical University, Sun-Yat Sen University, Third Military Medical University, and Central South University investigated the role of Bcl6 in regulating the tumorigenesis and immunosuppressive tumor microenvironment in a 4-nitroquinoline-1-oxide (4NQO)-induced mouse model of HNSCC.

To determine the role of Bcl6 in the immune response of Treg cells in HNSCC, the authors established a 4NQO-induced HNSCC model in Bcl6^flox/floxFoxp3^Cre (KO) and littermate Bcl6^flox/flox (WT) mice. The KO mice exhibited less weight loss, smaller and fewer tongue lesions, with nearly half of the lesions remaining at the dysplasia stage compared to the WT mice, suggesting that Bcl6 deficiency in Treg cells delays the malignant transformation of HNSCC.

Additionally, Bcl6 knockdown in Treg cells i) facilitates the priming and activation of CD8+ T cells in the draining lymph nodes (dLNs), which subsequently infiltrate into the tongue and display efficient effector function, ii) impairs the lineage stability and suppressive capacity of Treg cells, especially in the dLNs, and iii) down-regulates histone H3K4 trimethylation, leading to reduced Foxp3 expression, further impairing the lineage stability and suppressive function of Treg cells.

Further experiments showed that Bcl6 inhibitor FX1 significantly delays HNSCC progression, and its combination with PD-1/PD-L1 ICB exerts a more pronounced anti-tumor effect when compared to FX1 alone or anti-PD-L1 alone.

In conclusion, this study highlights the crucial role of Bcl6 in maintaining the lineage stability and suppressive function of Treg cells during HNSCC and shows that targeting Bcl6 represses murine HNSCC and augments the therapeutic efficacy of ICB therapy, “indicating that Bcl6 inhibition represents a promising strategy for clinical HNSCC treatment.”

Reference

Title of the Original Paper: Bcl6 controls the stability and suppressive function of regulatory T cells in head and neck squamous cell carcinoma

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2024.101505

Funding Information:

National Science Foundation for Outstanding Young Scholars of China (No. 82322031, 82122028)
National Natural Science Foundation of China (No. 82173094, 82372837)
National Science Foundation for Outstanding Young Scholars of Chongqing, China (No. CSTB2024NSCQ-JQX0008, CSTB2022NSCQ-JQX0015)
Natural Science Foundation of Chongqing Municipality, China (No. CSTB2023NSCQ-LZX0010, CSTB2023NSCQ-BHX0101, CSTB2023NSCQ-BHX0102)
Natural Science Foundation of Guang Dong, China (No. 2024A1515010375)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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