Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells
| Autor: | Shimon Sakaguchi, Hiroyoshi Nishikawa, Yuka Maeda, Yoshiko Takeuchi, Toshio Kitawaki, Elke Jäger, Fumihiko Monma, Danbee Ha, Yoshihiro Kameoka, Atsushi Tanaka, Naoto Takahashi, Naoyuki Katayama, Kohshi Ohishi, Shinsuke Noguchi, Yoshinori Shinohara, Kenichi Sawada, Keiko Iwaisako, Julia Karbach, Hiromasa Morikawa, Takuro Saito, Daisuke Sugiyama, Naoya Shigeta |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
Immunology Fusion Proteins bcr-abl Receptors Antigen T-Cell Apoptosis Mice Transgenic chemical and pharmacologic phenomena Mice SCID CD8-Positive T-Lymphocytes T-Lymphocytes Regulatory Article Tyrosine-kinase inhibitor Mice Immune system Antigen Blood cell depletion therapy Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans Immunology and Allergy Protein Kinase Inhibitors neoplasms Research Articles Mice Inbred BALB C Chemistry Immunity hemic and immune systems Imatinib medicine.disease Disease Models Animal Treatment Outcome Imatinib mesylate Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Colonic Neoplasms Imatinib Mesylate Cancer research Female CD8 medicine.drug Chronic myelogenous leukemia |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | As a novel type of anticancer reagent, imatinib inhibits not only BCR-ABL oncogenic protein but also LCK in T cells as an off-target, being able to selectively deplete mature T reg cells and thereby evoke effective immune responses to various cancers. This report addresses whether small molecules can deplete FoxP3-expressing regulatory T (T reg) cells, thereby augmenting antitumor immunity. Imatinib, a tyrosine kinase inhibitor of oncogenic BCR-ABL protein expressed by chronic myelogenous leukemia (CML) cells, possesses off-targets including LCK expressed in T cells. We showed that imatinib-treated CML patients in complete molecular remission (CMR) exhibited selective depletion of effector T reg (eT reg) cells and significant increase in effector/memory CD8+ T cells while non-CMR patients did not. Imatinib at CML-therapeutic concentrations indeed induced apoptosis specifically in eT reg cells and expanded tumor antigen–specific CD8+ T cells in vitro in healthy individuals and melanoma patients, and suppressed colon tumor growth in vivo in mice. Mechanistically, because of FoxP3-dependent much lower expression of LCK and ZAP-70 in T reg cells compared with other T cells, imatinib inhibition of LCK further reduced their TCR signal intensity, rendering them selectively susceptible to signal-deprived apoptotis. Taken together, eT reg cell depletion by imatinib is instrumental in evoking effective immune responses to various cancers. |
| Databáze: | OpenAIRE |
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