title: E(mu)-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction.
abstract: Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) Emu-TCL1 transgenic mouse model. With development of leukemia, Emu-TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young Emu-TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.
authors.affiliation: Department of Medical Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gullu
authors.initials: G
authors.lastname: Gorgun
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.forename: Tobias A W
authors.initials: TA
authors.lastname: Holderried
authors.forename: David
authors.initials: D
authors.lastname: Zahrieh
authors.forename: Rifca
authors.initials: R
authors.lastname: Le Dieu
authors.forename: Fenglong
authors.initials: F
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben