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.
Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells
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Atsushi Tanaka, Hiroyoshi Nishikawa, Shinsuke Noguchi, Daisuke Sugiyama, Hiromasa Morikawa, Yoshiko Takeuchi, Danbee Ha, Naoya Shigeta, Toshio Kitawaki, Yuka Maeda, Takuro Saito, Yoshinori Shinohara, Yoshihiro Kameoka, Keiko Iwaisako, Fumihiko Monma, Kohshi Ohishi, Julia Karbach, Elke Jäger, Kenichi Sawada, Naoyuki Katayama, Naoto Takahashi, Shimon Sakaguchi; Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells. J Exp Med 3 February 2020; 217 (2): e20191009. doi: https://doi.org/10.1084/jem.20191009
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