scholarly journals How does lenalidomide target the chronic lymphocytic leukemia microenvironment?

Blood ◽  
2014 ◽  
Vol 124 (14) ◽  
pp. 2184-2189 ◽  
Author(s):  
Arnon P. Kater ◽  
Sanne H. Tonino ◽  
Alexander Egle ◽  
Alan G. Ramsay
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Function ◽  
Lymphocytic Leukemia ◽  
T Cell Immunity ◽  
Cell Immunity ◽  
Immunomodulatory Drug ◽  
Targeted Drug ◽  
Potential Use ◽  
Clinical Strategy

Abstract Immunotherapy has emerged as a viable clinical strategy to harness endogenous antitumor T-cell immunity. Lenalidomide is an oral immunomodulatory drug that repairs antitumor T-cell function and is showing efficacy in ongoing chronic lymphocytic leukemia (CLL) and lymphoma clinical trials. This article focuses on advances in our understanding of its mechanism of action in the tumor microenvironment and provides a clinical update in CLL. Challenges associated with this drug and its potential use in the targeted drug treatment era are discussed.

scholarly journals Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

2021 ◽  
Author(s):  
Khalid W Kalim ◽  
Jun-Qi Yang ◽  
Mark Wunderlich ◽  
Vishnu Modur ◽  
Phuong Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Plasticity ◽  
Effector T Cell ◽  
Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

scholarly journals T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

Haematologica ◽  
2021 ◽  
Author(s):  
Fleur S. Peters ◽  
Jonathan C. Strefford ◽  
Eric Eldering ◽  
Arnon P. Kater
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy ◽  
High Expectations ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLLinduced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

scholarly journals Defective immunoregulatory T-cell function in chronic lymphocytic leukemia

Blood ◽  
1981 ◽  
Vol 58 (6) ◽  
pp. 1182-1189 ◽  
Author(s):  
T Han ◽  
H Ozer ◽  
ES Henderson ◽  
B Dadey ◽  
A Nussbaum-Blumenson ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Function ◽  
Lymphocytic Leukemia ◽  
T Cell Function

scholarly journals Decay-accelerating factor modulates induction of T cell immunity

2005 ◽  
Vol 201 (10) ◽  
pp. 1523-1530 ◽  
Author(s):  
Peter S. Heeger ◽  
Peter N. Lalli ◽  
Feng Lin ◽  
Anna Valujskikh ◽  
Jinbo Liu ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Function ◽  
Alternative Pathway ◽  
T Cell Immunity ◽  
Host Cells ◽  
Decay Accelerating Factor ◽  
Local Alternative ◽  
Cell Immunity ◽  
Pathway Activation

Decay-accelerating factor (Daf) dissociates C3/C5 convertases that assemble on host cells and thereby prevents complement activation on their surfaces. We demonstrate that during primary T cell activation, the absence of Daf on antigen-presenting cells (APCs) and on T cells enhances T cell proliferation and augments the induced frequency of effector cells. The effect is factor D- and, at least in part, C5-dependent, indicating that local alternative pathway activation is essential. We show that cognate T cell–APC interactions are accompanied by rapid production of alternative pathway components and down-regulation of Daf expression. The findings argue that local alternative pathway activation and surface Daf protein function respectively as a costimulator and a negative modulator of T cell immunity and explain previously reported observations linking complement to T cell function. The results could have broad therapeutic implications for disorders in which T cell immunity is important.

scholarly journals Defective immunoregulatory T-cell function in chronic lymphocytic leukemia

Blood ◽  
1981 ◽  
Vol 58 (6) ◽  
pp. 1182-1189 ◽  
Author(s):  
T Han ◽  
H Ozer ◽  
ES Henderson ◽  
B Dadey ◽  
A Nussbaum-Blumenson ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Function ◽  
Lymphocytic Leukemia ◽  
T Cell Function
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