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

Katie E Hurst,Zhiwei Ye,Nathan Dolloff,Jessica E Thaxton,Kiley A Lawrence,Lety Reyes Angeles,Danyelle M Townsend,Jie Zhang

doi:10.3390/cells8121514

Abstract

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.

Highlights

Recent advances in cancer immunotherapy have given rise to new therapeutic classes that dually target tumor cells directly and promote anti-tumor immunity by modulating T cell function [1,2].Targeting the endoplasmic reticulum (ER) stress response is a strategy to induce a pro-death response in tumor cells that leads to control of tumors [3,4]
Inhibition of protein disulfide isomerase (PDI) led to an accumulation of unfolded/misfolded proteins demonstrated by increased ubiquitination, rapid cell death through activation of the unfolded protein response (UPR), and enhanced efficacy of FDA-approved proteasome inhibitors [7,8]
We demonstrate the surprising finding that PDI inhibition attenuates the UPR and promotes viability of healthy T cells, whereas it activates the UPR and restricts survival in oncogenic T cells

Summary

Introduction

Recent advances in cancer immunotherapy have given rise to new therapeutic classes that dually target tumor cells directly and promote anti-tumor immunity by modulating T cell function [1,2].Targeting the endoplasmic reticulum (ER) stress response is a strategy to induce a pro-death response in tumor cells that leads to control of tumors [3,4]. Cells 2019, 8, 1514 conditional gene deletion of PERK, we demonstrated that PERK restricts T cell anti-tumor capability [6]. Together, these data suggest that targeting the unfolded protein response (UPR) may be a therapeutic avenue to develop effective new therapies for cancer patients. Leveraging the UPR-mediated cell death pathway led to the development of a new class of therapeutics that target protein disulfide isomerase (PDI), a redox-dependent protein folding enzyme with isomerase and chaperone activity. Inhibition of PDI led to an accumulation of unfolded/misfolded proteins demonstrated by increased ubiquitination, rapid cell death through activation of the UPR, and enhanced efficacy of FDA-approved proteasome inhibitors [7,8]. PDI is an emerging drug target in oncology, and, while the anti-tumor effects of PDI inhibition have been well documented, the consequence of PDI modulation on healthy immune cells has not been assessed

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