Universität zu Köln

Golumba-Nagy, Viktoria, Kuehle, Johannes, Hombach, Andreas A. and Abken, Hinrich (2018). CD28-zeta CAR T Cells Resist TGF-beta Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop. Mol. Ther., 26 (9). S. 2218 - 2231. CAMBRIDGE: CELL PRESS. ISSN 1525-0024

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Abstract

Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-beta, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-zeta CAR, but not with a 4-1BB-zeta CAR, resist TGF-beta-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-beta resistance; deleting the LCK-beta inding motif in the CD28 CAR abolished both IL-2 secretion and TGF-beta resistance, while IL-2 add-back restored TGF-beta resistance. Other g-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2 deficient CD28DLCK-zeta CAR T cells with a hybrid IL-7 receptor to provide IL-2R beta chain signaling upon IL-7 binding. Such modified T cells showed improved CAR T cell activity against TGF-beta(+) tumors. Data draw the concept that an autocrine loop resulting in IL-2R signaling can make CAR T cells more potent in staying active against TGF-beta(+) solid tumors.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Golumba-Nagy, Viktoria UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuehle, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Hombach, Andreas A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-173213
DOI:	10.1016/j.ymthe.2018.07.005
Journal or Publication Title:	Mol. Ther.
Volume:	26
Number:	9
Page Range:	S. 2218 - 2231
Date:	2018
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1525-0024
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR-BETA; CHIMERIC ANTIGEN RECEPTORS; CD28 COSTIMULATION; TUMOR MICROENVIRONMENT; SELECTIVE EXPANSION; PERIPHERAL-BLOOD; CANCER; LYMPHOCYTES; PROLIFERATION; INTERLEUKIN-7 Multiple languages Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17321