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Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant.

ABSTRACT: A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teff activation. In contrast, blockade of OX40L signaling has the capacity to partially control Teff activation despite maintaining Treg function. We used the nonhuman primate graft-versus-host disease (GVHD) model to probe the efficacy of combinatorial immunomodulation with sirolimus and the OX40L-blocking antibody KY1005. Our results demonstrate significant biologic activity of KY1005 alone (prolonging median GVHD-free survival from 8 to 19.5 days), as well as marked, synergistic control of GVHD with KY1005 + sirolimus (median survival time, >100 days; P < 0.01 compared to all other regimens), which was associated with potent control of both TH/TC1 (T helper cell 1/cytotoxic T cell 1) and TH/TC17 activation. Combined administration also maintained Treg reconstitution [resulting in an enhanced Treg/Teff ratio (40% over baseline) in the KY1005/sirolimus cohort compared to a 2.9-fold decrease in the unprophylaxed GVHD cohort]. This unique immunologic signature resulted in transplant recipients that were able to control GVHD for the length of analysis and to down-regulate donor/recipient alloreactivity despite maintaining anti-third-party responses. These data indicate that combined OX40L blockade and sirolimus represents a promising strategy to induce immune balance after transplant and is an important candidate regimen for clinical translation.

SUBMITTER: Tkachev V

PROVIDER: S-EPMC5681253 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant.

Tkachev Victor V Furlan Scott N SN Watkins Benjamin B Hunt Daniel J DJ Zheng Hengqi Betty HB Panoskaltsis-Mortari Angela A Betz Kayla K Brown Melanie M Schell John B JB Zeleski Katie K Yu Alison A Kirby Ian I Cooley Sarah S Miller Jeffrey S JS Blazar Bruce R BR Casson Duncan D Bland-Ward Phil P Kean Leslie S LS

Science translational medicine 20170901 408

A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadeq ...[more]

PMID: 28931653

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Project description:Background Accumulation of Foxp3+ regulatory T (Treg) cells in the tumor often represents an important mechanism for cancer immune evasion and a critical barrier to anti-tumor immunity and immunotherapy. Many tumor-infiltrating Treg cells display an activated phenotype and express the transcription factor Blimp1. However, the specific impact of these Blimp1+ Treg cells and their follicular regulatory T (TFR) cell subset on tumor and the underlying mechanisms of action are not yet well-explored. Methods Various transplantable tumor models were established in immunocompetent wild-type mice and mice with a Foxp3-specific ablation of Blimp1. Tumor specimens from patients with metastatic melanoma and TCGA datasets were analyzed to support the potential role of Treg and TFR cells in tumor immunity. In vitro culture assays and in vivo adoptive transfer assays were used to understand how Treg, TFR cells and antibody responses influence tumor control. RNA sequencing and NanoString analysis were performed to reveal the transcriptome of tumor-infiltrating Treg cells and tumor cells, respectively. Finally, the therapeutic effects of anti-PD-1 treatment combined with the disruption of Blimp1+ Treg activity were evaluated. Results Blimp1+ Treg and TFR cells were enriched in the tumors, and higher tumoral TFR signatures indicated increased risk of melanoma metastasis. Deletion of Blimp1 in Treg cells resulted in impaired suppressive activity and a reprogramming into effector T-cells, which were largely restricted to the tumor-infiltrating Treg population. This destabilization combined with increased anti-tumor effector cellular responses, follicular helper T-cell expansion, enhanced tumoral IgE deposition and activation of macrophages secondary to dysregulated TFR cells, remodeled the tumor microenvironment and delayed tumor growth. The increased tumor immunogenicity with MHC upregulation improved response to anti-PD-1 blockade. Mechanistically, Blimp1 enforced intratumoral Treg cells with a unique transcriptional program dependent on Eomesodermin (Eomes) expression; deletion of Eomes in Blimp1-deficient Treg cells restored tumor growth and attenuated anti-tumor immunity. Conclusions These findings revealed Blimp1 as a new critical regulator of tumor-infiltrating Treg cells and a potential target for modulating Treg activity to treat cancer. Our study has also revealed two FCERIA-containing immune signatures as promising diagnostic or prognostic markers for melanoma patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-021-01450-3.

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Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant.

Publications

Combined OX40L and mTOR blockade controls effector T cell activation while preserving T<sub>reg</sub> reconstitution after transplant.

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