TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis

Peres, Raphael Sanches; Donate, Paula B.; Talbot, Jhimmy; Cecílio, Nerry T.; Lobo, Patricia R.; Machado, Caio Cavalcante; Lima, Keli; Oliveira, Renê Donizeti Ribeiro de; Carregaro, Vanessa; Nakaya, Hidehiko; Cunha, Thiago M.; Alves‐Filho, José C.; Liew, Foo Y.; Louzada‐Júnior, Paulo; Cunha, Fernando Q.

doi:10.1016/j.jaut.2018.01.004

Cited by 43 publications

(30 citation statements)

References 36 publications

(53 reference statements)

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“…We did detect a moderate increase in CD73 and the expression of both CD39 and CD73 can be increased by TGF-β [70,71]. Though CD73 is expressed intracellularly in humans, surface expression can be induced upon activation with high-dose IL-2 therapy [72].…”

Section: Discussionmentioning

confidence: 71%

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

2020

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Background: The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. Most immunotherapies rely on induction of CD8+ tumor-specific cytotoxic T cells that are capable of directly killing cancer cells. Tumors, however, utilize a variety of mechanisms that can suppress anti-tumor immunity. CD4+ regulatory T cells can directly inhibit cytotoxic T cell activity and these cells can be recruited, or induced, by cancer cells allowing escape from immune attack. The use of ionizing radiation as a treatment for cancer has been shown to enhance anti-tumor immunity by several mechanisms including immunogenic tumor cell death and phenotypic modulation of tumor cells. Less is known about the impact of radiation directly on suppressive regulatory T cells. In this study we investigate the direct effect of radiation on human T REG viability, phenotype, and suppressive activity. Results: Both natural and TGF-β1-induced CD4+ T REG cells exhibited increased resistance to radiation (10 Gy) as compared to CD4+ conventional T cells. Treatment, however, decreased Foxp3 expression in natural and induced T REG cells and the reduction was more robust in induced T REGS. Radiation also modulated the expression of signature iT REG molecules, inducing increased expression of LAG-3 and decreased expression of CD25 and CTLA-4. Despite the disconcordant modulation of suppressive molecules, irradiated iT REGS exhibited a reduced capacity to suppress the proliferation of CD8+ T cells. Conclusions: Our findings demonstrate that while human T REG cells are more resistant to radiation-induced death, treatment causes downregulation of Foxp3 expression, as well as modulation in the expression of T REG signature molecules associated with suppressive activity. Functionally, irradiated TGF-β1-induced T REGS were less effective at inhibiting CD8+ T cell proliferation. These data suggest that doses of radiotherapy in the hypofractionated range could be utilized to effectively target and reduce T REG activity, particularly when used in combination with cancer immunotherapies.

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Section: Discussionmentioning

confidence: 71%

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

2020

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“…Consistent with an important role for TGF-β in regulating CD39 expression, carriers of at least one mutant allele for a TGFBR2 SNP (rs1431131) showed a significant reduction of CD39 mRNA levels in CD4 + T cells. 102 Extracellular ATP and adenosine signaling further regulate Treg survival and function. Notably, P2×7 is highly expressed in Tregs.…”

Section: Cd39 and Immunosuppression Through Extracellular Vesicles (Evs)mentioning

confidence: 99%

On the mechanism of anti-CD39 immune checkpoint therapy

Allard

Stagg

2020

J Immunother Cancer

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With the coming of age of cancer immunotherapy, the search for new therapeutic targets has led to the identification of immunosuppressive adenosine as an important regulator of antitumor immunity. This resulted in the development of selective inhibitors targeting various components of the adenosinergic pathway, including small molecules antagonists targeting the high affinity A2A adenosine receptor and low affinity A2B receptor, therapeutic monoclonal antibodies (mAbs) and small molecules targeting CD73 and therapeutic mAbs targeting CD39. As each regulator of the adenosinergic pathway present non-overlapping biologic functions, a better understanding of the mechanisms of action of each targeted approach should accelerate clinical translation and improve rational design of combination treatments. In this review, we discuss the potential mechanisms-of-action of anti-CD39 cancer therapy and potential toxicities that may emerge from sustained CD39 inhibition. Caution should be taken, however, in extrapolating data from gene-targeted mice to patients treated with blocking anti-CD39 agents. As phase I clinical trials are now underway, further insights into the mechanism of action and potential adverse events associated with anti-CD39 therapy are anticipated in coming years.

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“…Uma delas é a artrite juvenil idiopática e a artrite reumatoide. Para a primeira, estamos preparando um manuscrito para submissão e para a segunda, um artigo já foi publicado em 2018 (106) no qual participamos como colaborador.…”

Section: Artrite Idiopática Juvenilunclassified

Usando a imunologia de sistemas para entender os mecanismos moleculares de doenças e vacinas

Nakaya¹

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TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis

Cited by 43 publications

References 36 publications

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

On the mechanism of anti-CD39 immune checkpoint therapy

Usando a imunologia de sistemas para entender os mecanismos moleculares de doenças e vacinas

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