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The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity.

Cell | Dec 1, 2016

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.

Pubmed ID: 27912060 RIS Download

Mesh terms: Animals | Cancer Vaccines | Gene Deletion | Immune Tolerance | Immunotherapy | Mice | Mice, Inbred BALB C | Mice, Inbred C3H | Mice, Inbred C57BL | Neoplasms | Protein-Serine-Threonine Kinases | Signal Transduction | Toll-Like Receptors | Tumor Suppressor Proteins

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Associated grants

  • Agency: NIAID NIH HHS, Id: HHSN272201400051C
  • Agency: NEI NIH HHS, Id: R01 EY022611
  • Agency: NIGMS NIH HHS, Id: R01 GM051586
  • Agency: NCI NIH HHS, Id: R35 CA196878

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