ABSTRACT
Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathways is critical to enhance the efficacy of ibrutinib. Here, we focus on the BCL2 anti-apoptotic pathway. In a tissue microarray of 62 MCL samples, BCL2 expression positively correlated with BTK expression. Increased levels of BCL2 were shown to be due to a defect in protein degradation because of no or little expression of the E3 ubiquitin ligase FBXO10, as well as transcriptional upregulation through BTK-mediated canonical nuclear factor-κB activation. RNA-seq analysis confirmed that a set of anti-apoptotic genes (for example, BCL2, BCL-XL and DAD1) was downregulated by BTK short hairpin RNA. The downregulated genes also included those that are critical for B-cell growth and proliferation, such as BCL6, MYC, PIK3CA and BAFF-R. Targeting BCL2 by the specific inhibitor ABT-199 synergized with ibrutinib in inhibiting growth of both ibrutinib-sensitive and -resistant cancer cells in vitro and in vivo. These results suggest co-targeting of BTK and BCL2 as a new therapeutic strategy in MCL, especially for patients with primary resistance to ibrutinib.
Subject(s)
F-Box Proteins/genetics , Gene Expression Regulation, Neoplastic , Lymphoma, Mantle-Cell/genetics , Lymphoma, Mantle-Cell/metabolism , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Agammaglobulinaemia Tyrosine Kinase , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cluster Analysis , Gene Expression Profiling , Humans , Lymphoma, Mantle-Cell/pathology , NF-kappa B/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, Antigen, B-Cell/metabolism , Signal Transduction , Sulfonamides/pharmacologyABSTRACT
Interleukin-7 (IL-7) is required for the development and survival of T cells and plays a critical role in modulating T-cell homeostasis. This review will address current understanding of IL-7 biology, review recent clinical experiences and discuss potential future clinical applications of IL-7, or IL-7 blockade, in the setting of disease.
Subject(s)
Immunotherapy/methods , Interleukin-7/immunology , T-Lymphocytes/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , HIV Infections/immunology , HIV Infections/therapy , Homeostasis/immunology , Humans , Neoplasms/immunology , Neoplasms/therapy , Randomized Controlled Trials as TopicABSTRACT
Subsets of natural killer (NK) cells are characterized by the expression of inhibitory and/or stimulatory receptors specific for major histocompatibility complex (MHC) class I determinants. In mice, these include the Ly49 family of molecules. One mechanism by which tumor cells may evade NK cell killing is by expressing the appropriate MHC class I and binding inhibitory Ly49 receptors. Therefore, the question of whether blocking the interaction between the Ly49 inhibitory receptors on NK and MHC class I cells on tumor cells augments antitumor activity was investigated. Blockade of Ly49C and I inhibitory receptors using F(ab')(2) fragments of the 5E6 monoclonal antibody (mAb) resulted in increased cytotoxicity against syngeneic tumors and decreased tumor cell growth in vitro. The effect of 5E6 F(ab')(2) was specific for the MHC of the tumor, as the use of F(ab')(2) of the mAb against Ly49G2 failed to increase NK activity. Treatment of leukemia-bearing mice with 5E6 F(ab')(2) fragments or adoptive transfer of NK cells treated ex vivo with the F(ab')(2) resulted in significant increases in survival. These results demonstrate that blockade of NK inhibitory receptors enhances antitumor activity both in vitro and in vivo, suggesting that NK inhibitory receptors can be responsible for diminishing antitumor responses. Therefore, strategies to block inhibitory receptors may be of potential use in increasing the efficacy of immunotherapy. (Blood. 2001;97:3132-3137)
