Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade

Abstract 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 trans...

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Autores principales:	Michael L. Dixon, Lin Luo, Sadashib Ghosh, Jeffrey M. Grimes, Jonathan D. Leavenworth, Jianmei W. Leavenworth
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Anti-tumor immunity Humoral antibody response IgE Effector regulatory T-cells Follicular regulatory T-cells Treg lineage stability Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/30ce81d646da475cb6af87c87c5a8680
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spelling	oai:doaj.org-article:30ce81d646da475cb6af87c87c5a86802021-11-21T12:02:25ZRemodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade10.1186/s12943-021-01450-31476-4598https://doaj.org/article/30ce81d646da475cb6af87c87c5a86802021-11-01T00:00:00Zhttps://doi.org/10.1186/s12943-021-01450-3https://doaj.org/toc/1476-4598Abstract 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.Michael L. DixonLin LuoSadashib GhoshJeffrey M. GrimesJonathan D. LeavenworthJianmei W. LeavenworthBMCarticleAnti-tumor immunityHumoral antibody responseIgEEffector regulatory T-cellsFollicular regulatory T-cellsTreg lineage stabilityNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Cancer, Vol 20, Iss 1, Pp 1-24 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Anti-tumor immunity Humoral antibody response IgE Effector regulatory T-cells Follicular regulatory T-cells Treg lineage stability Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Anti-tumor immunity Humoral antibody response IgE Effector regulatory T-cells Follicular regulatory T-cells Treg lineage stability Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Michael L. Dixon Lin Luo Sadashib Ghosh Jeffrey M. Grimes Jonathan D. Leavenworth Jianmei W. Leavenworth Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
description	Abstract 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.
format	article
author	Michael L. Dixon Lin Luo Sadashib Ghosh Jeffrey M. Grimes Jonathan D. Leavenworth Jianmei W. Leavenworth
author_facet	Michael L. Dixon Lin Luo Sadashib Ghosh Jeffrey M. Grimes Jonathan D. Leavenworth Jianmei W. Leavenworth
author_sort	Michael L. Dixon
title	Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
title_short	Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
title_full	Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
title_fullStr	Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
title_full_unstemmed	Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade
title_sort	remodeling of the tumor microenvironment via disrupting blimp1+ effector treg activity augments response to anti-pd-1 blockade
publisher	BMC
publishDate	2021
url	https://doaj.org/article/30ce81d646da475cb6af87c87c5a8680
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Remodeling of the tumor microenvironment via disrupting Blimp1+ effector Treg activity augments response to anti-PD-1 blockade

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