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The Eμ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia

A Preclinical Tool to Investigate and Target PD-L1/PD-1-Mediated CD8 T-Cell Dysfunction
  • Fabienne McClanahan
  • John Gribben
Living reference work entry

Abstract

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and, despite the availability of targeted therapies, remains incurable. An important hallmark is severe immune deficiency caused by complex cancer-induced T-cell defects, leading to ineffective antitumor immune responses and susceptibility to infections. The immune checkpoint molecules PD-1 (mainly expressed on activated immune effector cells) and PD-L1 (expressed on antigen-presenting and microenvironmental cells including tumor cells) have emerged as important mediators of T-cell suppression, not only in CLL but also in other malignancies. Several clinical studies demonstrate that targeting PDL-1/PD-1 interactions produces significant responses. However, similar studies are notably absent in CLL, and the effect of PDL-1/PD-1 blockade on restoring CLL-induced immune dysfunction is not understood. Transgenic Eμ-TCL1 mice have been extensively validated as an adequate preclinical model of aggressive human CLL and are especially suitable to mirror CLL-induced T-cell defects. In addition, the confounding effect of aging on T-cell dysfunction can be overcome by adoptive transfer of murine CLL cells into young disease-free mice. Both in transgenic mice and in mice after adoptive transfer, developing CLL is associated with specific T-cell subset alterations, phenotypic changes, and functional defects. CD8+ T cells in leukemic mice are characterized as a functionally heterogeneous population, in which subsets of cells are able to exert effector functions despite PD-1 expression. PD-L1-blocking antibody effectively controls disease and reverses global T-cell defects even in cells expressing PD-1, providing a strong rationale to explore PD-L1/PD-1 targeting in clinical trials, potentially in combination with novel agents.

Keywords

Chronic lymphocytic leukemia Eμ-TCL1 mouse model Immune deficiency PD-L1/PD-1 Immunotherapy 

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Barts Cancer Institute, Centre for Haemato-OncologyQueen Mary University of LondonLondonUK
  2. 2.Wexner Medical Center, Comprehensive Cancer CenterThe Ohio State UniversityColumbusUSA

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