Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity

Maarten A. Ligtenberg, Dimitrios Mougiakakos, Madhura Mukhopadhyay, Kristina Witt, Alvaro Lladser, Markus Chmielewski, Tobias Riet, Hinrich Abken, Rolf Kiessling

Research output: Contribution to journalArticlepeer-review

119 Citations (Scopus)

Abstract

Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3ζ chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress-mediated repression.

Original languageEnglish
Pages (from-to)759-766
Number of pages8
JournalJournal of Immunology
Volume196
Issue number2
DOIs
Publication statusPublished - 15 Jan 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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