Universität zu Köln

Ligtenberg, Maarten A., Mougiakakos, Dimitrios, Mukhopadhyay, Madhura, Witt, Kristina, Lladser, Alvaro, Chmielewski, Markus, Riet, Tobias, Abken, Hinrich and Kiessling, Rolf (2016). Coexpressed Catalase Protects Chimeric Antigen Receptor-Redirected T Cells as well as Bystander Cells from Oxidative Stress-Induced Loss of Antitumor Activity. J. Immunol., 196 (2). S. 759 - 767. BETHESDA: AMER ASSOC IMMUNOLOGISTS. ISSN 1550-6606

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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 CD3 zeta 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ligtenberg, Maarten A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mougiakakos, Dimitrios UNSPECIFIED UNSPECIFIED UNSPECIFIED Mukhopadhyay, Madhura UNSPECIFIED UNSPECIFIED UNSPECIFIED Witt, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Lladser, Alvaro UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Riet, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Kiessling, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-287213
DOI:	10.4049/jimmunol.1401710
Journal or Publication Title:	J. Immunol.
Volume:	196
Number:	2
Page Range:	S. 759 - 767
Date:	2016
Publisher:	AMER ASSOC IMMUNOLOGISTS
Place of Publication:	BETHESDA
ISSN:	1550-6606
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HYDROGEN-PEROXIDE; ACTIVATED GRANULOCYTES; DECREASED EXPRESSION; CANCER PATIENTS; BREAST-CANCER; SUPPRESSION; LYMPHOCYTES; MOLECULES; SURVIVAL; THERAPY Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28721