Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis

Abstract

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3 + cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

ZBTB Transcription Factors: Key Regulators of the Development, Differentiation and Effector Function of T Cells

“…Moreover, BCL6 upregulates CXCR5 in Foxp3 + Treg cells, and thereby endows these so-called T follicular regulatory (Tfr) cells with the capacity to migrate towards the B cell follicular to limit the magnitude of GC responses ( 126 , 127 ). In addition, BCL6 maintains Foxp3 expression and promotes the suppressive ability of tumor-infiltrating Treg cells, and thus high BCL6 levels in Treg cells represent a poor prognosis marker in patients with colorectal cancer & melanoma ( 128 ). Of note, how BCL6 maintains the lineage stability and functional fitness of Treg cells specifically in tumor microenvironment remains unsolved.…”

Identification of a Novel Immune-Related lncRNA CTD-2288O8.1 Regulating Cisplatin Resistance in Ovarian Cancer Based on Integrated Analysis

“…Consistent with our prediction, it has been confirmed that the downregulation of lncRNA GAS5 increases the binding of the transcription factor CEBPB to the promoter of GDF15 and promotes the progress and chemotherapy resistance of OC ( Guo and Wang, 2019 ). BCL6 is involved in regulating the immune response of tumor-infiltrating regulatory T cells during the occurrence and development of various tumors ( Li et al, 2020 ). CEBPA activation affected the regulation of immune-suppressive myeloid cells to cause antitumor response ( Hashimoto et al, 2021 ).…”

Follicular regulatory T cell biology and its role in immune-mediated diseases

“…4,5 In addition, Bcl6 seems to be expressed in Treg cell subsets other than Tfr cells especially those residing in parenchymal tissues and tumor. 23,24 Moreover, the microenvironment may affect the receptor expressions on Tfr cells, with an example that murine Tfr cells in the spleen have higher PD-1 but lower ICOS expressions as compared with those located in the draining lymph nodes (dLNs). 22 Collectively, identifications of Tfr cells solely via cytometric staining may be insufficient.…”

“…For Bcl6, unlike Tfh cells where Bcl6 is crucial for cell development, the absolute dependence of Tfr cells on Bcl6 has been suggested but not strictly proved 4,5 . In addition, Bcl6 seems to be expressed in Treg cell subsets other than Tfr cells especially those residing in parenchymal tissues and tumor 23,24 . Moreover, the microenvironment may affect the receptor expressions on Tfr cells, with an example that murine Tfr cells in the spleen have higher PD‐1 but lower ICOS expressions as compared with those located in the draining lymph nodes (dLNs) 22 .…”