Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells

Chakraborty, Paramita; Chatterjee, Shilpak; Kesarwani, Pravin; Thyagarajan, Krishnamurthy; Iamsawat, Supinya; Dalheim, Annika V.; Nguyen, Hung; Selvam, Shanmugam Panneer; Nasarre, Patrick; Scurti, Gina; Hardiman, Gary; Maulik, Nilanjana; Ball, Lauren E.; Gangaraju, Vamsi K.; Rubinstein, Mark P.; Klauber-DeMore, Nancy; Hill, Elizabeth G.; Öğretmen, Besim; Yu, Xue-Zhong; Nishimura, Michael I.; Mehrotra, Shikhar

doi:10.1074/jbc.ra118.006753

Cited by 33 publications

(17 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thioredoxin is one of the main antioxidants in the cellular redox system that functions as a scavenger for ROS, with its primary function being to reduce oxidized cysteine residues and cleave disulfide bonds (7,8). Elevated levels of thioredoxin often correlate with immune activation, regulating the survival of immune cells (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells

Yang

Neo

Chen

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells

Yang

Neo

Chen

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…More recently, these efforts encompass modulating host immunity. T cells with an abundance of cell surface free thiols [14] or overexpression of thioredoxin [15] improve their capacity to control tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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

Hurst

Lawrence

Angeles

et al. 2019

Cells

View full text Add to dashboard Cite

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.

show abstract

“…7 ). It has been suggested that strategies for increasing the antioxidant capacity of anti-tumor T cells, by activating Trx-1, can modulate their immune-metabolic phenotype leading to improved immunotherapeutic control of established tumors [ 47 ]. In this context, ADAM17cyto can be promoting a more antioxidant state, but there is also an increase of ADAM17 shedding.…”

Section: Discussionmentioning

confidence: 99%

ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

et al. 2020

View full text Add to dashboard Cite

The activity of Thioredoxin-1 (Trx-1) is adjusted by the balance of its monomeric, active and its dimeric, inactive state. The regulation of this balance is not completely understood. We have previously shown that the cytoplasmic domain of the transmembrane protein A D isintegrin A nd M etalloprotease 17 (ADAM17cyto) binds to Thioredoxin-1 (Trx-1) and the destabilization of this interaction favors the dimeric state of Trx-1. Here, we investigate whether ADAM17 plays a role in the conformation and activation of Trx-1. We found that disrupting the interacting interface with Trx-1 by a site-directed mutagenesis in ADAM17 (ADAM17cyto F730A ) caused a decrease of Trx-1 reductive capacity and activity. Moreover, we observed that ADAM17 overexpressing cells favor the monomeric state of Trx-1 while knockdown cells do not. As a result, there is a decrease of cell oxidant levels and ADAM17 sheddase activity and an increase in the reduced cysteine-containing peptides in intracellular proteins in ADAM17cyto overexpressing cells. A mechanistic explanation that ADAM17cyto favors the monomeric, active state of Trx-1 is the formation of a disulfide bond between Cys 824 at the C-terminal of ADAM17cyto with the Cys 73 of Trx-1, which is involved in the dimerization site of Trx-1. In summary, we propose that ADAM17 is able to modulate Trx-1 conformation affecting its activity and intracellular redox state, bringing up a novel possibility for positive regulation of thiol isomerase activity in the cell by mammalian metalloproteinases.

show abstract

Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells

Cited by 33 publications

References 53 publications

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells

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

ADAM17 cytoplasmic domain modulates Thioredoxin-1 conformation and activity

Contact Info

Product

Resources

About