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.
Highlights
Regulatory T (Treg) cells, with the master regulator Foxp3, represent a functional distinct subset of CD4 T cells, which are endowed with the ability of immune suppression and play a pivotal role in maintaining immune-homeostasis and autoimmune diseases [1,2,3]
To investigate the role of B cell lymphoma 6 (Bcl6) in Treg cells immune response during tumorigenesis, we first evaluated the expression pattern of Bcl6 in Treg cells in TME and tumor Draining lymph nodes (dLNs) of wild-type (WT) mice intravenously implanted with B16-F10 melanoma cells
We confirmed that tumor infiltrating Treg cells expressed higher level of Bcl6 than Treg cells derived from tumor dLNs and spleens (Figure 1B) in mice challenged with MC-38 cells subcutaneously
Summary
Regulatory T (Treg) cells, with the master regulator Foxp (forkhead box P3), represent a functional distinct subset of CD4 T cells, which are endowed with the ability of immune suppression and play a pivotal role in maintaining immune-homeostasis and autoimmune diseases [1,2,3]. Foxp3+ Treg cells exert their effector functions through a variety of molecular mechanisms. Treg cells constitutively express the high-affinity heterotrimeric interleukin 2 (IL2) receptor, known as CD25, which further bind to and consume IL2 from their surroundings, compromising its effects on non-Foxp effector T cells (Teff) [4, 5]. Treg cells express high level of cytotoxic T lymphocyte antigen 4 (CTLA4), which can bind to CD80/CD86 on antigen presenting cells (APCs) and thereby transmitting suppressive signals to these cells and reducing their capacity to activate Teff cells [6]. Bcl Preserves Treg Function higher affinity to CD80/CD86 than that of CD28, competing with this co-stimulatory receptor, which further disrupts the priming and/or activation of Teff cells [7]. Treg cells can produce immunosuppressive cytokines, such as TGFβ, IL10, and IL35 [8], which will downregulate the activity of APCs and Teff cells, and secrete granzymes and perforin that can directly kill these cells [9]
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