TY - JOUR
T1 - Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction
AU - Gorgun, Gullu
AU - Ramsay, Alan G.
AU - Holderried, Tobias A.W.
AU - Zahrieh, David
AU - Dieu, Rifca Le
AU - Liu, Fenglong
AU - Quackenbush, John
AU - Croce, Carlo M.
AU - Gribben, John G.
PY - 2009/4/14
Y1 - 2009/4/14
N2 - Preclinical animal models have largely ignored the immune-sup-pressive 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.
AB - Preclinical animal models have largely ignored the immune-sup-pressive 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.
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U2 - 10.1073/pnas.0901166106
DO - 10.1073/pnas.0901166106
M3 - Article
C2 - 19332800
AN - SCOPUS:65549151712
SN - 0027-8424
VL - 106
SP - 6250
EP - 6255
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -