Thioredoxin-1 improves the immunometabolic phenotype of antitumor T cells

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

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)
5 Downloads (Pure)

Abstract

Adoptive transfer of tumor epitope–reactive T cells has emerged as a promising strategy to control tumor growth. However, chronically-stimulated T cells expanded for adoptive cell transfer are susceptible to cell death in an oxidative tumor microenvironment. Because oxidation of cell-surface thiols also alters protein functionality, we hypothesized that increasing the levels of thioredoxin (Trx), an antioxidant molecule facilitating reduction of proteins through cysteine thiol-disulfide exchange, in T cells will promote their sustained antitumor function. Using pre-melanosome protein (Pmel)–Trx1 transgenic mouse-derived splenic T cells, flow cytometry, and gene expression analysis, we observed here that higher Trx expression inversely correlated with reactive oxygen species and susceptibility to T-cell receptor restimulation or oxidation-mediated cell death. These Trx1-overex-pressing T cells exhibited a cluster of differentiation 62Lhi (CD62Lhi) central memory-like phenotype with reduced glucose uptake (2-NBDGlo) and decreased effector function (interferon lo). Furthermore, culturing tumor-reactive T cells in the presence of recombinant Trx increased the dependence of T cells on mitochondrial metabolism and improved tumor control. We conclude that strategies for increasing the antioxidant capacity of antitumor T cells modulate their immunometabolic phenotype leading to improved immunotherapeutic control of established tumors.

Original languageEnglish
Pages (from-to)9198-9212
Number of pages15
JournalJournal of Biological Chemistry
Volume294
Issue number23
DOIs
Publication statusPublished - 10 Apr 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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