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.
journal_name
Proc Natl Acad Sci U S Aauthors
Gorgun G,Ramsay AG,Holderried TA,Zahrieh D,Le Dieu R,Liu F,Quackenbush J,Croce CM,Gribben JGdoi
10.1073/pnas.0901166106subject
Has Abstractpub_date
2009-04-14 00:00:00pages
6250-5issue
15eissn
0027-8424issn
1091-6490pii
0901166106journal_volume
106pub_type
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