Dataset Information

CD28-ζ CAR T Cells Resist TGF-β Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop.

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-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-β resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-β resistance, while IL-2 add-back restored TGF-β resistance. Other γ-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2 deficient CD28ΔLCK-ζ CAR T cells with a hybrid IL-7 receptor to provide IL-2R β chain signaling upon IL-7 binding. Such modified T cells showed improved CAR T cell activity against TGF-β⁺ 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-β⁺ solid tumors.

SUBMITTER: Golumba-Nagy V

PROVIDER: S-EPMC6127517 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD28-ζ CAR T Cells Resist TGF-β Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop.

Golumba-Nagy Viktória V Kuehle Johannes J Hombach Andreas A AA Abken Hinrich H

Molecular therapy : the journal of the American Society of Gene Therapy 20180710 9

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-β, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-ζ CAR, but not with a 4-1BB-ζ CAR, resist TGF-β-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 recepto ...[more]

PMID: 30055872

Similar Datasets

Project description:IntroductionImmunotherapy has revolutionized cancer treatment, and Chimeric Antigen Receptor T cell therapy (CAR-T) is a groundbreaking approach. Traditional second-generation CAR-T therapies have achieved remarkable success in hematological malignancies, but there is still room for improvement, particularly in developing new targeting strategies. To address this limitation, engineering T cells with multi-target universal CARs (UniCARs) based on monomeric streptavidin has emerged as a versatile approach in the field of anti-tumor immunotherapy. However, no studies have been conducted on the importance of the intracellular signaling domains of such CARs and their impact on efficiency and specificity.MethodHere, we developed second-generation and third-generation UniCARs based on an extracellular domain comprising an affinity-enhanced monomeric streptavidin, in addition to CD28 and 4-1BB co-stimulatory intracellular domains. These UniCAR structures rely on a biotinylated intermediary, such as an antibody, for recognizing target antigens. In co-culture assays, we performed a functional comparison between the third-generation UniCAR construct and two second-generation UniCAR variants, each incorporating either the CD28 or 4-1BB as co-stimulatory domain.ResultsWe observed that components in culture media could inhibit the binding of biotinylated antibodies to monomeric streptavidin-CARs, potentially compromising their efficacy. Furthermore, third-generation UniCAR-T cells showed robust cytolytic activity against cancer cell lines upon exposure to specific biotinylated antibodies like anti-CD19 and anti-CD20, underscoring their capability for multi-targeting. Importantly, when assessing engineered UniCAR-T cell activation upon encountering their target cells, third-generation UniCAR-T cells exhibited significantly enhanced specificity compared to second-generation CAR-T cells.DiscussionFirst, optimizing culture conditions would be essential before deploying UniCAR-T cells clinically. Moreover, we propose that third-generation UniCAR-T cells are excellent candidates for preclinical research due to their high specificity and multi-target anti-tumor cytotoxicity.

Dataset Information

CD28-ζ CAR T Cells Resist TGF-β Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop.

Publications

CD28-ζ CAR T Cells Resist TGF-β Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets