Cell
Volume 167, Issue 6, 1 December 2016, Pages 1525-1539.e17
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Article
The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity

https://doi.org/10.1016/j.cell.2016.11.005Get rights and content
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Highlights

  • LATS1/2 deletion in tumor cells inhibits tumor growth in vivo

  • Loss of LATS1/2 induces anti-tumor immune responses

  • Extracellular vesicles from LATS1/2-null tumors stimulate the host TLRs-IFN pathway

  • LATS1/2 deletion enhances tumor vaccine efficacy

Summary

Poorly immunogenic tumor cells evade host immunity and grow even in the presence of an intact immune system, but the complex mechanisms regulating tumor immunogenicity have not been elucidated. Here, we discovered an unexpected role of the Hippo pathway in suppressing anti-tumor immunity. We demonstrate that, in three different murine syngeneic tumor models (B16, SCC7, and 4T1), loss of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in tumor cells inhibits tumor growth. Tumor regression by LATS1/2 deletion requires adaptive immune responses, and LATS1/2 deficiency enhances tumor vaccine efficacy. Mechanistically, LATS1/2-null tumor cells secrete nucleic-acid-rich extracellular vesicles, which induce a type I interferon response via the Toll-like receptors-MYD88/TRIF pathway. LATS1/2 deletion in tumors thus improves tumor immunogenicity, leading to tumor destruction by enhancing anti-tumor immune responses. Our observations uncover a key role of the Hippo pathway in modulating tumor immunogenicity and demonstrate a proof of concept for targeting LATS1/2 in cancer immunotherapy.

Keywords

Hippo
LATS
YAP
TAZ
cancer immunity
immunotherapy
B16 melanoma
exosome
interferon
Toll-like receptor

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