title: The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity.
abstract: 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.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Moroishi
authors.affiliation: Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; College of Medicine, Jiaxing University, Jiaxing 314001, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Pan
authors.affiliation: Department of Pathology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Holt
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D017353:Gene Deletion; D007108:Immune Tolerance; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019496:Cancer Vaccines; D051193:Toll-Like Receptors; D025521:Tumor Suppressor Proteins; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: B16 melanoma; Hippo; LATS; TAZ; Toll-like receptor; YAP; cancer immunity; exosome; immunotherapy; interferon