Peripheral T Cells Are the Therapeutic Targets of Glucocorticoids in Experimental Autoimmune Encephalomyelitis

Wüst, Simone; Brandt, Jens van den; Tischner, Denise; Kleiman, Anna; Tuckermann, Jan; Gold, Ralf; Lühder, Fred; Reichardt, Holger M.

doi:10.4049/jimmunol.180.12.8434

Cited by 172 publications

(226 citation statements)

References 40 publications

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“…51,52 Additionally, in studies of experimental autoimmune encephalomyelitis (EAE), a well-established rodent model of multiple sclerosis (MS), dexamethasone treatment induced apoptosis and inhibited the CNS migration of peripheral, bystander T cells with limited impact on CNS-resident, antigen-specific T cells. 35,53 Taken together, these data suggest there may be variability of corticosteroid’s influence on CNS-resident vs. peripheral T cells, and the current study’s findings demonstrate that anti-PD-1-mediated immune responses against intracranial tumors may potentially go undeterred in the setting of corticosteroids. Corticosteroid use did not correlate with the density of infiltrating T cells in a large cohort of patients with brain metastases.…”

Section: Discussionmentioning

confidence: 52%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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Section: Discussionmentioning

confidence: 52%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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“…Glucocorticoids were shown to moderate the initial inflammatory response and decrease leukocyte infiltration at the inflammation site (29). Glucocorticoids induce apoptosis of peripheral lymphocytes (30) and thus prevent the infiltration of T cells into the CNS and subsequent neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

et al. 2014

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“…Because of the deletion of the GR in the T cell lineage, thymocytes from GR flox/flox lckCre +/2 mice are protected from apoptosis induced by increased levels of corticosterone (13,18) (Fig. 2B, 2C).…”

Section: Resultsmentioning

confidence: 99%

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Uhmann

Brandt

Dittmann

et al. 2011

The Journal of Immunology

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We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch-deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type–specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling.

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Peripheral T Cells Are the Therapeutic Targets of Glucocorticoids in Experimental Autoimmune Encephalomyelitis

Cited by 172 publications

References 40 publications

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

PET Imaging of Disease Progression and Treatment Effects in the Experimental Autoimmune Encephalomyelitis Rat Model

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

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