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

Cells. 2019 Nov 26;8(12):1514. doi: 10.3390/cells8121514.


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.

Keywords: ER stress; T cell; immunotherapy; protein disulfide isomerase; redox; tumor cell; ubiquitin; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival / genetics
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress*
  • Immunotherapy, Adoptive* / methods
  • Interleukin-15 / metabolism
  • Melanoma, Experimental
  • Mice
  • Mice, Transgenic
  • Neoplasms / etiology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Oxidation-Reduction
  • Oxidative Stress
  • Protein Disulfide-Isomerases / antagonists & inhibitors
  • Protein Disulfide-Isomerases / genetics*
  • Protein Disulfide-Isomerases / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Unfolded Protein Response


  • Interleukin-15
  • Protein Disulfide-Isomerases