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

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.

Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy

“…They identified the stress response p38 MAP kinase as a key driver involved in preventing T cell mediated tumor immunity (155). This finding reinforces previous studies that elegantly demonstrated that ER stress, a target regulated by p38, impairs intratumoral T cell protein translation of cytotoxic molecules and regulates mitochondrial and T cell exhaustion (156)(157)(158)(159). Nonetheless, the current efforts exploring inhibition of these key signaling pathways in vitro may provide TIL and CAR T cell with enhanced bioenergetics, persistence and anti-tumor capacity during their expansion.…”

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas

“…PDIA5 regulates the unfolded protein response (UPR) signaling pathway by activating ATF6α ( 28 ), whereby UPR regulates tumor cell survival. Other research has found that PDI inhibition could impair tumorigenic T cells and enhance normal T cell function ( 29 ). Based on the aforementioned findings, we speculated that PDIA5 correlated with histopathology grades and immune infiltration of gliomas, and could be a potential prognostic molecule.…”

Endoplasmic Reticulum-Associated Degradation-Dependent Processing in Cross-Presentation and Its Potential for Dendritic Cell Vaccinations: A Review

“…It is also possible that artificial disulfide bond formation in extracellular proteins increases CP efficiency. Recent research has shown that PDI inhibitors induce cancer-specific apoptosis in addition to the activation of cancer-specific T cells and the expansion of memory T cells in a mouse model [136]. In this experiment, cancer-specific T cells were activated by the addition of cancer-specific peptides; therefore, this is not the result of the progression of CP efficiency.…”