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

The Journal of experimental medicine, ISSN: 1540-9538, Vol: 217, Issue: 2
2020
  • 45
    Citations
  • 0
    Usage
  • 52
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    45
    • Citation Indexes
      44
    • Policy Citations
      1
      • Policy Citation
        1
  • Captures
    52

Article Description

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.

Bibliographic Details

Tanaka, Atsushi; Nishikawa, Hiroyoshi; Noguchi, Shinsuke; Sugiyama, Daisuke; Morikawa, Hiromasa; Takeuchi, Yoshiko; Ha, Danbee; Shigeta, Naoya; Kitawaki, Toshio; Maeda, Yuka; Saito, Takuro; Shinohara, Yoshinori; Kameoka, Yoshihiro; Iwaisako, Keiko; Monma, Fumihiko; Ohishi, Kohshi; Karbach, Julia; Jäger, Elke; Sawada, Kenichi; Katayama, Naoyuki; Takahashi, Naoto; Sakaguchi, Shimon

Rockefeller University Press

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