Deletion of LATS1/2 Hippo Pathway Kinases Enhances Antitumor Immunity

Hippo pathway activation results in phosphorylation and activation of the LATS1/2 kinases, which phosphorylate and inactivate the YAP/TAZ transcriptional coactivators. This pathway is generally considered tumor suppressive, although context-dependent oncogenic roles have been described, but the role of Hippo signaling in tumor growth in the context of an intact immune system has not been well elucidated. Moroishi and colleagues found that LATS1/2 depletion had opposing effects on tumor cell growth in vitro and in vivo, suggesting a possible effect on antitumor immunity. In vitro, loss of Lats1/2 in melanoma, head and neck squamous cell carcinoma, and breast cancer cells reduced YAP phosphorylation and enhanced anchorage-independent growth. However, in vivo, Lats1/2 deletion inhibited the growth of melanoma, head and neck squamous cell carcinoma, and breast cancer xenografts, revealing an unexpected oncogenic role for LATS1/2 in multiple tumor types. LATS1/2-deficient tumor cells displayed massive inflammatory cell infiltration, suggesting that adaptive immune responses may clear LATS1/2-deficient tumors. In vivo, LATS1/2 loss resulted in an enhanced tumor-specific humoral immune response and CD8⁺ T-cell activation, indicative of robust antitumor immunity. LATS1/2 loss improved tumor vaccine efficacy, with immunization with Lats1/2-deficient cells protecting against wild-type tumor growth via an adaptive immune response, demonstrating that LATS1/2 loss enhances tumor cell immunogenicity. LATS1/2 depletion results in hyperactivation of YAP/TAZ, and, similarly, overexpression of YAP or TAZ reduced tumor growth in vivo, indicating that LATS1/2 loss may suppress tumor growth in part through YAP/TAZ-dependent transcription. Moreover, LATS1/2-deficient tumor cells secreted nucleic-acid rich extracellular vesicles that induced type I interferon (IFN) signaling and promoted antitumor immunity. The finding that LATS1/2 loss promotes an antitumor immune response reveals an unexpected oncogenic effect of the Hippo pathway kinases and suggests the possibility of targeting LATS1/2 in cancer immunotherapy.

Moroishi T, Hayashi T, Pan WW, Fujita Y, Holt MV, Qin J, et al. The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell 2016 Dec 1 [Epub ahead of print].