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    • Successful immune escape will be then followed by cancer

    2021-09-18

    Successful immune escape will be then followed by cancer development, along with which immunocytes infiltration occurs. While some immunocytes are born to sweep away the malignancy, others aim to neutralize the lethality and sustain immune anergy and tolerance [59,60]. And the latter one is well represented by myeloid-derived suppressor ll-37 (MDSCs) [60]. In a related research, due to incompetent Hippo in prostate cancer, enriched YAP was accused of its ability to upregulate Cxcl5, a cancer-secreted chemokine during MDSC recruitment (Fig. 3b). There is a positive track between YAP and an MDSC signature as well, confirming the emerging role of Hippo in immunology [61]. Besides MDSC, Tregs are another population in the inflammatory environment that functions to suppress tumor killing. Although lack of direct connection, infiltrated Tregs were reported to be positively correlated with YAP expression [62]. Meanwhile, hepatocytes with dysfunctional Hippo were reported to develop into malignancy [56]. In this study, MST1/2 dKO-associated YAP overexpression directly and drastically augmented hepatocytic monocyte chemoattractant protein-1 (MCP1) secretion, which facilitated hepatic macrophage infiltration during pro-cancerous microenvironment formation, leading to HCC progression (Fig. 3c). It is noteworthy that macrophages with MST1/2-depletion are more active in secreting cytokines yet weak in phagocytosis [63]. Although the inflammation arises, it still fosters the cancer cells well and let them thrive. Another important member that participates in the regulation of immune surveillance is programmed death-ligand 1 (PD-L1), whose interaction with PD-1 induces and maintains T cell tolerance, which prolongs tumor survival eventually [64]. Recent works also indicated the interplays between Hippo-YAP cascade and PD-L1 [57,58]. Apart from driving tumor growth, YAP directly promotes PD-L1 expression, disabling the host monitoring system towards malignancy (Fig. 3d). On the other hand, in terms of YAP-independent cancer cells, one of the latest studies has sketched a pro-inflammation figure of Hippo [22]. Differs from the mechanisms mentioned above, loss of Hippo component LATS1/2 triggers an anti-cancer response. Despite that, this time, the response is stimulated by production of extracellular vesicles (EVs) instead of hyper-activation of YAP. This novel idea has clearly demonstrated that LATS1/2-deleted tumor cells invite robust immunity to obliterate themselves. Accordingly, LATS1/2 dKO cells were found to secret more nucleic acid-rich EVs, which motivated Toll-like Receptors (TLRs). As a result, the downstream of the endogenous nucleic-acid-sensing pathways, in which TLRs are involved, are activated. TLRs induce pro-inflammatory cytokines and type I IFN that maturating dendritic cells. The maturated dendritic cells then promote antigen cross-presentation, expanding CD8+ T cell clones [65]. It is the cytotoxic immunocytes that are awakened within this inflammatory process, which ensures the successful execution of immune clearance.
    Hippo-related targeted immunotherapy Theoretically, Hippo pathway fulfills the task of YAP cytoplasmic sequestration, so that YAP fails to bind with its transcriptional factors and promote proliferative gene expression [13,15]. Therefore, keeping YAP out of the nuclei becomes an essential step [66], which is also supported by Guo X et al., except for the fact that they support it from an immunological aspect [54]. They indicated that blocking the YAP-TEAD interaction dampened the recruitment of TIC-associated macrophages, releasing the protective effect for TIC and making way for those tumor-killing cells. Yet, Moroishi, et al. hold another opinion: rather than aiming at YAP, they proposed to knockout LATS1/2 [22]. In spite of the fact that, as the upstream of YAP, LATS1/2 functions to prevent YAP nuclear translocation, but its knockout arouses an anti-cancer response that is much stronger than the overgrowth effect endowed by activated YAP. Nevertheless, the cell models in this study were less persuasive regarding YAP-driven carcinogenesis. Even though the cells with LATS1/2 dKO displayed stronger proliferative ability in the in vitro experiment, their growth is not originally dependent on YAP overexpression, or Hippo dysfunction.