Eμ-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

G Gorgun, AG Ramsay… - Proceedings of the …, 2009 - National Acad Sciences
G Gorgun, AG Ramsay, TAW Holderried, D Zahrieh, R Le Dieu, F Liu, J Quackenbush
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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) Eμ-TCL1 transgenic mouse model. With development of
leukemia, Eμ-TCL1 transgenic mice developed functional T-cell defects and alteration of …
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) Eμ-TCL1 transgenic mouse model. With development of leukemia, Eμ-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 Eμ-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.
National Acad Sciences