T follicular helper cell-mediated IL-21 production suppresses FOXP3 expression of T follicular regulatory-like cells in diffuse large B cell lymphoma patients

Ma, Xiaomei; Zha, Jun; He, Junna; Huang, Jinlong; Wu, Wei-Hao; Tian, Pan; Bian, Qian; Yu, Lian; Jiang, Yunxia; Xu, Bing

doi:10.1016/j.humimm.2020.05.008

Cited by 8 publications

(11 citation statements)

References 24 publications

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“…Tregs and Tfr differed in expression of transcription factors and cytokines, supporting the notion that they exert different functions. This study further described a mechanism whereby IL-21 secreted by Tfh regulated the expression of FoxP3 and IL-10 in Tfr in DLBCL patient samples ( 98 ).…”

Section: T Follicular Regulatory Cellsmentioning

confidence: 71%

“…Another recent study demonstrated that CD4 + CXCR5 + T cells from DLBCL patients could be divided into Tfr or Tfh based on whether they were CD25 + or CD25 - respectively ( 98 ). Tregs and Tfr differed in expression of transcription factors and cytokines, supporting the notion that they exert different functions.…”

Section: T Follicular Regulatory Cellsmentioning

confidence: 99%

“…Nurse-like cells represent tumor-associated macrophages in CLL that support CLL survival and proliferation ( 99 ). Interestingly, coculture of nurse-like cells with CLL T cells increased Tfr percent and elevated expression of activation and proliferation markers including CD69, PD-1, CTLA-4, TGF-β, IL-10 and Ki67 ( 98 ). Collectively these studies indicate that Tfr in lymphoma and CLL are functionally distinct from Tregs.…”

Section: T Follicular Regulatory Cellsmentioning

confidence: 99%

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Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

et al. 2022

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Regulatory T cells (Tregs) are responsible for maintaining immune homeostasis by controlling immune responses. They can be characterized by concomitant expression of FoxP3, CD25 and inhibitory receptors such as PD-1 and CTLA-4. Tregs are key players in preventing autoimmunity and are dysregulated in cancer, where they facilitate tumor immune escape. B-cell lymphoid malignancies are a group of diseases with heterogenous molecular characteristics and clinical course. Treg levels are increased in patients with B-cell lymphoid malignancies and correlate with clinical outcomes. In this review, we discuss studies investigating Treg immunobiology in B-cell lymphoid malignancies, focusing on clinical correlations, mechanisms of accumulation, phenotype, and function. Overarching trends suggest that Tregs can be induced directly by tumor cells and recruited to the tumor microenvironment where they suppress antitumor immunity to facilitate disease progression. Further, we highlight studies showing that Tregs can be modulated by novel therapeutic agents such as immune checkpoint blockade and targeted therapies. Treg disruption by novel therapeutics may beneficially restore immune competence but has been associated with occurrence of adverse events. Strategies to achieve balance between these two outcomes will be paramount in the future to improve therapeutic efficacy and safety.

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Section: T Follicular Regulatory Cellsmentioning

confidence: 71%

Section: T Follicular Regulatory Cellsmentioning

confidence: 99%

Section: T Follicular Regulatory Cellsmentioning

confidence: 99%

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Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

et al. 2022

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“…This would be consistent with an immunosuppressive tumour microenvironment where DLBCL cells may directly restrict T FH functions through increased surface PD-L1 expression and autocrine IL-10 secretion, acquiring immune evasion characteristics that resemble Breg-like functions [ 58 , 59 , 61 , 63 , 67 , 72 , 73 ]. These IL-21-impaired T FH cells in DLBCL may also promote a cytokine switch towards IL-10 production by T FR cells [ 169 , 171 ], further contributing to lymphoma maintenance and progression.…”

Section: The Pd-1/pd-l1 Axis In Dlbclmentioning

confidence: 99%

The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

Garcia-Lacarte

Grijalba

Melchor

et al. 2021

Cancers

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Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (TFH) and regulatory T (TFR) or B (Breg) cells are involved in positive selection of GC B cells and may result critically in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of TFR cells and limiting IL-21-mediated anti-tumour functions of TFH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8+ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.

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“…Additionally, the crosstalk between lymphoma B cells and Tfh cells increases the release of CCL17 and CCL22, which induces the preferential migration of regulatory T cells (Treg) and IL-4 producing CD4 + T cells, stimulating more chemokine release thus creating an immune suppressive TME that promotes tumor survival and growth [ 23 , 24 ]. Another study divided Tfh cells into Tfr-like subsets (CD4 + CD25 + CXCR5 + ) and Tfh CD25 - subset (CD4 + CD25 - CXCR5 + ) [ 25 ]. The difference between these two groups was associated with the higher expression of Blimp1, Foxp3, IL-10, TGF-β, and lower levels of IL-21 in Tfr-like CD25 + cells compared to Tfh CD25 - cells [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Insights into the tumor microenvironment of B cell lymphoma

Ansell

Mondello

2022

J Exp Clin Cancer Res

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The standard therapies in lymphoma have predominantly focused on targeting tumor cells with less of a focus on the tumor microenvironment (TME), which plays a critical role in favoring tumor growth and survival. Such an approach may result in increasingly refractory disease with progressively reduced responses to subsequent treatments. To overcome this hurdle, targeting the TME has emerged as a new therapeutic strategy. The TME consists of T and B lymphocytes, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and other components. Understanding the TME can lead to a comprehensive approach to managing lymphoma, resulting in therapeutic strategies that target not only cancer cells, but also the supportive environment and thereby ultimately improve survival of lymphoma patients. Here, we review the normal function of different components of the TME, the impact of their aberrant behavior in B cell lymphoma and the current TME-direct therapeutic avenues.

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T follicular helper cell-mediated IL-21 production suppresses FOXP3 expression of T follicular regulatory-like cells in diffuse large B cell lymphoma patients

Cited by 8 publications

References 24 publications

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

Insights into the tumor microenvironment of B cell lymphoma

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