Coexpressed Catalase Protects Chimeric Antigen Receptor–Redirected T Cells as well as Bystander Cells from Oxidative Stress–Induced Loss of Antitumor Activity

Journal of Immunology - Tập 196 Số 2 - Trang 759-766 - 2016
Maarten A. Ligtenberg1, Dimitrios Mougiakakos2, Madhura Mukhopadhyay1, Kristina Witt1, Álvaro Lladser3, Markus Chmielewski4,5, Tobias Riët4,5, Hinrich Abken4,5, Rolf Kiessling1
1*Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden;
2†Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen–Nuremberg, 91054 Erlangen Germany;
3‡Laboratorio de Inmunoterapia Génica, Fundación Ciencia y Vida, 7780272 Santiago, Chile;
4§Labor Tumorgenetik, Klinik I für Innere Medizin, Universität zu Köln, 50931 Cologne, Germany; and
5¶Zentrum für Molekulare Medizin Köln, Universität zu Köln, 50931 Cologne, Germany

Tóm tắt

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.

Từ khóa


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Journal of Immunology

Tập 196 Số 2

759-766

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