Format

Send to

Choose Destination
Cell. 2016 Dec 1;167(6):1525-1539.e17. doi: 10.1016/j.cell.2016.11.005.

The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity.

Author information

1
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
3
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.
4
Department of Pathology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
5
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: kuguan@ucsd.edu.

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.

KEYWORDS:

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

PMID:
27912060
PMCID:
PMC5512418
DOI:
10.1016/j.cell.2016.11.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center