Metabolic reprogramming augments potency of human pSTAT3–inhibited iTregs to suppress alloreactivity

Walton, Kelly; Fernandez, Mario R.; Sagatys, Elizabeth M.; Reff, Jordan; Kim, Jongphil; Lee, Marie Catherine; Kiluk, John V.; Hui, Jane Yuet Ching; McKenna, David H.; Hupp, Meghan; Forster, Colleen L.; Linden, Michael A.; Lawrence, Harshani R.; Pidala, Joseph; Pavletić, Steven Z.; Blazar, Bruce R.; Sebti, Saı̈d M.; Cleveland, John L.; Anasetti, Claudio; Betts, Brian C.

doi:10.1172/jci.insight.136437

Cited by 13 publications

(13 citation statements)

References 64 publications

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“…Beyond calcineurin inhibitors, cell-based immune suppression is increasingly being studied in GVHD prevention. We and others have shown that Tregs offer potent and potentially antigenspecific inhibition of alloreactive T cells (14)(15)(16). Past clinical trials incorporating Tregs in GVHD prophylaxis have proven that cell-mediated immune suppression delivers safe and effective control over donor T cells without impairing GVL (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease

Shrestha¹,

Walton²,

Reff³

et al. 2020

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease

Shrestha¹,

Walton²,

Reff³

et al. 2020

Journal of Clinical Investigation

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“…Further, iTregs treated with STAT3 inhibitor exhibited dramatically enhanced suppression ability and achieved stability via high levels of FOXP3 demethylation (91). Furthermore, STAT3 phosphorylationinhibited iTregs have potent function in preventing xenogeneic GVHD by reducing excess immune responses caused by alloreactive T cells (92). Zinc supplementation may also increase iTreg numbers while maintaining their stability by prolonging FOXP3 expression (93).…”

Section: Tregs' Expansion For Gvhd Therapy Expansion Ex Vivomentioning

confidence: 99%

Regulatory T Cells in GVHD Therapy

Guo

Wang

et al. 2021

Front. Immunol.

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Graft versus host disease (GVHD) is a common complication and the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pharmacological immunosuppression used in GVHD prophylaxis and treatment lacks specificity and can increase the likelihood of infection and relapse. Regulatory T lymphocytes (Tregs) play a vital role in restraining excessive immune responses and inducing peripheral immune tolerance. In particular, clinical trials have demonstrated that Tregs can prevent and treat GVHD, without increasing the risk of relapse and infection. Hence, adoptive transfer of Tregs to control GVHD using their immunosuppressive properties represents a promising therapeutic approach. To optimally apply Tregs for control of GVHD, a thorough understanding of their biology is necessary. In this review, we describe the biological characteristics of Tregs, including how the stability of FOXP3 expression can be maintained. We will also discuss the mechanisms underlying Tregs-mediated modulation of GVHD and approaches to effectively increase Tregs’ numbers. Finally, we will examine the developing trends in the use of Tregs for clinical therapy.

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“…Phospho-STAT3 inhibited peripheral Treg generation in murine aGVHD ( 110 ). Inhibition of STAT3 phosphorylation (pSTAT3) in human Tregs enhanced the suppressive capacity and stability of iTregs ( 111 ). Notably, pSTAT3- inhibited iTregs significantly reduced xenogeneic GVHD compared to vehicle control, while sparing donor GVT responses.…”

Section: Metabolic Effects Of Coinhibitory Pathway Blockade and Cellular Therapy In Allo-hsctmentioning

confidence: 99%

Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease

et al. 2021

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The therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the development of graft-versus-host disease (GVHD). In GVHD, rigorous pre-conditioning regimen resets the immune landscape and inflammatory milieu causing immune dysregulation, characterized by an expansion of alloreactive cells and a reduction in immune regulatory cells. In acute GVHD (aGVHD), the release of damage- and pathogen- associated molecular patterns from damaged tissue caused by the conditioning regimen sets the stage for T cell priming, activation and expansion further exacerbating tissue injury and organ damage, particularly in the gastrointestinal tract. Studies have shown that donor T cells utilize multiple energetic and biosynthetic pathways to mediate GVHD that can be distinct from the pathways used by regulatory T cells for their suppressive function. In chronic GVHD (cGVHD), donor T cells may differentiate into IL-21 producing T follicular helper cells or tissue resident T helper cells that cooperate with germinal center B cells or memory B cells, respectively, to produce allo- and auto-reactive antibodies with subsequent tissue fibrosis. Alternatively, donor T cells can become IFN- γ/IL-17 cytokine expressing T cells that mediate sclerodermatous skin injury. Patients refractory to the first line standard regimens for GVHD treatment have a poor prognosis indicating an urgent need for new therapies to restore the balance between effector and regulatory immune cells while preserving the beneficial graft-versus-tumor effect. Emerging data points toward a role for metabolism in regulating these allo- and auto-immune responses. Here, we will discuss the preclinical and clinical data available on the distinct metabolic demands of acute and chronic GVHD and recent efforts in identifying therapeutic targets using metabolomics. Another dimension of this review will examine the changing microbiome after allo-HSCT and the role of microbial metabolites such as short chain fatty acids and long chain fatty acids on regulating immune responses. Lastly, we will examine the metabolic implications of coinhibitory pathway blockade and cellular therapies in allo-HSCT. In conclusion, greater understanding of metabolic pathways involved in immune cell dysregulation during allo-HSCT may pave the way to provide novel therapies to prevent and treat GVHD.

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Metabolic reprogramming augments potency of human pSTAT3–inhibited iTregs to suppress alloreactivity

Cited by 13 publications

References 64 publications

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease

Regulatory T Cells in GVHD Therapy

Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease

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