Tyrosine kinase inhibitor imatinib augments tumor immunity by depleting effector regulatory T cells

• DOI: 10.1084/jem.20191009
• Publication Date: 2019-11-08T19:45:21Z
• Authors: 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
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Fusion Proteins, bcr-abl; Immunity; Receptors, Antigen, T-Cell; Apoptosis; Mice, Transgenic; Mice, SCID; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Cell Line, Tumor; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Colonic Neoplasms; Imatinib Mesylate; Animals; Humans; Female; Protein Kinase Inhibitors; Research Articles

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.