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- W4313368428 abstract "Abstract Targeting of regulatory T cells (Treg) is a long-sought approach to overcome tumor immune evasion. However, systemic depletion of Treg likely causes autoimmune diseases. Indeed, we have recently reported that Treg-specific homozygous deletion of Cdc42 GTPase caused a drastic reduction in Treg numbers and systemic inflammatory diseases. Here we show that heterozygous deletion of Cdc42 (Cdc42+/−) did not affect Treg homeostasis but destabilized them, leading to effector T cell reprogramming in these Treg and impaired function in suppressing effector T cells. Accordingly, Cdc42+/− mice had increased effector T cells. Intriguingly, Cdc42+/− mice showed a remarkable suppression of growth of mouse colon and pancreatic tumors, with no noticeable autoimmunity. Mechanistically, Cdc42+/− Treg exhibited a significantly increased expression of carbonic anhydrase 1 (CA1), reversal of which by CA1 shRNA or a CA inhibitor restored Treg stability and tumor growth. Pharmacological inactivation of Cdc42 by a chemical inhibitor, CASIN, destabilized wild type (WT) Treg in mice and triggered anti-tumor T cell immunity, with no detectable autoimmune responses. CASIN also destabilized WT Treg in vitro and adoptive transfer of CASIN-treated Treg with congenic effector T cells into Rag1−/− mice suppressed tumor growth, demonstrating that CASIN-induced Treg instability caused tumor suppression. Combined CASIN and Anti-PD-1 antibody led to an additive suppression of mouse tumors as well as human tumors in human immune cell-reconstituted NSG-SGM3 mice. Collectively, our data suggest that rational targeting of Cdc42-regulated Treg stability holds promise in counteracting tumor immune evasion." @default.
- W4313368428 created "2023-01-06" @default.
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- W4313368428 date "2020-05-01" @default.
- W4313368428 modified "2023-09-25" @default.
- W4313368428 title "Rational targeting of Cdc42 GTPase destabilizes Treg to promote anti-tumor T cell immunity" @default.
- W4313368428 doi "https://doi.org/10.4049/jimmunol.204.supp.244.5" @default.
- W4313368428 hasPublicationYear "2020" @default.
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