Hippo Signaling in Cancer Immunity

Hippo Signaling in Cancer Immunity The Hippo pathway has evolutionarily conserved roles in limiting the size of organs [1]. It is a kinase cascade regulating transcriptional complexes in response to various upstream signals (Box 1). At the cellular level, the Hippo pathway inhibits cell proliferation and stemness, while promoting apoptosis in a cell autonomous manner. In mice, dysregulation of the Hippo pathway causes a marked increase in cell number and, thus, robust enlargement of organs and initiation of tumorigenesis. Recent reports demonstrated critical roles of the Hippo pathway in cancer immunity. Contrary to its tumor-suppressor function, loss of LATS1/2 was found to inhibit subcutaneous xenograft tumor growth in syngeneic mice by enhancing antitumor immunity [2]. LATS1/2 knockout (KO) induces a type-I interferon response noncell autonomously in a manner dependent on the Toll-like receptor (TLR)-MYD88/TRIF pathway via secretion of nucleic acid-rich extracellular vesicles. By contrast, LATS1/2 KO, MST1/2 KO, as well as expression of active YAP in murine hepatocytes in vivo, recruit type II macrophages through the induction of cytokines CCL2 and CSF1, leading to the establishment of an immunosuppressive microenvironment (Figure 1A) 3, 4. Knockdown of CCL2 and CSF1 blocks macrophage recruitment and diminishes liver tumorigenesis due to clearance of YAP-active tumor-initiating 7α,25-dihydroxy Cholesterol mg by immunosurveillance [3]. These findings indicate that functions of the Hippo pathway in tumorigenesis are not confined to tumor cells, but instead involve modulation of the tumor immune microenvironment. However, it is still unclear how seemingly opposite effects of LATS1/2 KO in promoting or repressing cancer immunosurveillance can be reconciled. Oncogenic driving forces of distinct tumors might tip the balance between the tumor-promoting and tumor-suppressive effects of LATS1/2 KO. In tumors driven by YAP activation, the profound cell autonomous effect together with anti-immunosurveillance functions might strongly promote tumorigenesis. However, in cancers driven by other growth-promoting pathways, the immune-stimulating functions of LATS1/2 ablation might elicit an overall tumor-suppressive effect. In addition, the composition of immune cells and factors in a tissue context could be a determining factor in the immune response induced by LATS1/2 KO. Thus, the experimental models used to study the Hippo pathway in cancer immunity could be critical.
Hippo Signaling in Innate Immunity Innate immunity is the nonspecific first line of defense against foreign pathogens. While seemingly unrelated to growth control, innate immunity was recently reported as being regulated by the Hippo pathway. It was found that canonical Hippo signaling is activated upon infection in fat bodies, the Drosophila immune organ producing antimicrobial peptides, by the Toll-Myd88-Pelle (IRAK1 homolog) pathway due to inhibition of the Hippo phosphatase STRIPAK PP2A complex [5]. Thus, the antimicrobial response is enhanced through decreased expression of Cactus (the IκB homolog), a Yki target gene (Figure 1B). In mouse macrophages, infection by Mycobacterium tuberculosis also activates MST1/2 phosphorylation in a TLR2-IRAK1/4-dependent manner [6]. However, in this case, MST1/2 promotes innate immunity response independently of the canonical Hippo pathway downstream effectors by directly activating IRF3 (Figure 1B). Furthermore, Mst1/2 in myeloid cells could also promote direct killing of phagocytosed bacteria by inducing juxtaposition of phagosomes with reactive oxygen species (ROS)-producing mitochondria through Rac activation (Figure 1B) [7]. Taken together, the above studies reveal critical roles of the Hippo pathway in antibacterial immunity through several different mechanisms. How these mechanisms coordinate in different contexts still waits to be determined. Recent reports also demonstrated roles of YAP/TAZ in antagonizing the antiviral response through direct binding of IRF3 or TBK1 8, 9. Thus, further clarification of the physiological roles and mechanisms of Hippo signaling in antiviral immunity is needed.