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Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors

Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeuti...

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Autores principales: Hurst, Katie E., Lawrence, Kiley A., Reyes Angeles, Lety, Ye, Zhiwei, Zhang, Jie, Townsend, Danyelle M., Dolloff, Nathan, Thaxton, Jessica E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953024/
https://www.ncbi.nlm.nih.gov/pubmed/31779147
http://dx.doi.org/10.3390/cells8121514
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author Hurst, Katie E.
Lawrence, Kiley A.
Reyes Angeles, Lety
Ye, Zhiwei
Zhang, Jie
Townsend, Danyelle M.
Dolloff, Nathan
Thaxton, Jessica E.
author_facet Hurst, Katie E.
Lawrence, Kiley A.
Reyes Angeles, Lety
Ye, Zhiwei
Zhang, Jie
Townsend, Danyelle M.
Dolloff, Nathan
Thaxton, Jessica E.
author_sort Hurst, Katie E.
collection PubMed
description Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control.
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spelling pubmed-69530242020-01-23 Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors Hurst, Katie E. Lawrence, Kiley A. Reyes Angeles, Lety Ye, Zhiwei Zhang, Jie Townsend, Danyelle M. Dolloff, Nathan Thaxton, Jessica E. Cells Article Effective cancer therapies simultaneously restrict tumor cell growth and improve anti-tumor immune responses. Targeting redox-dependent protein folding enzymes within the endoplasmic reticulum (ER) is an alternative approach to activation of the unfolded protein response (UPR) and a novel therapeutic platform to induce malignant cell death. E64FC26 is a recently identified protein disulfide isomerase (PDI) inhibitor that activates the UPR, oxidative stress, and apoptosis in tumor cells, but not normal cell types. Given that targeting cellular redox homeostasis is a strategy to augment T cell tumor control, we tested the effect of E64FC26 on healthy and oncogenic T cells. In stark contrast to the pro-UPR and pro-death effects we observed in malignant T cells, we found that E64FC26 improved viability and limited the UPR in healthy T cells. E64FC26 treatment also diminished oxidative stress and decreased global PDI expression in normal T cells. Oxidative stress and cell death are limited in memory T cells and we found that PDI inhibition promoted memory traits and reshaped T cell metabolism. Using adoptive transfer of tumor antigen-specific CD8 T cells, we demonstrate that T cells activated and expanded in the presence of E64FC26 control tumor growth better than vehicle-matched controls. Our data indicate that PDI inhibitors are a new class of drug that may dually inhibit tumor cell growth and improve T cell tumor control. MDPI 2019-11-26 /pmc/articles/PMC6953024/ /pubmed/31779147 http://dx.doi.org/10.3390/cells8121514 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hurst, Katie E.
Lawrence, Kiley A.
Reyes Angeles, Lety
Ye, Zhiwei
Zhang, Jie
Townsend, Danyelle M.
Dolloff, Nathan
Thaxton, Jessica E.
Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors
title Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors
title_full Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors
title_fullStr Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors
title_full_unstemmed Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors
title_short Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors
title_sort endoplasmic reticulum protein disulfide isomerase shapes t cell efficacy for adoptive cellular therapy of tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953024/
https://www.ncbi.nlm.nih.gov/pubmed/31779147
http://dx.doi.org/10.3390/cells8121514
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