Abstract
Hippo pathway with its main molecule YAP is a crucial pathway for development, tissue homeostasis, wound healing, tissue regeneration, and cancer. In this review, we discuss the multiple effects of the YAP/Hippo pathway in the immune system and cancer. We analyzed a series of effects: extracellular vesicles enhanced immunity through inhibition of LATS1/2, ways of modulation of the tumor microenvironment, YAP- and TAZ-mediated upregulation of PDL1, high expression of YAP and PDL1 in EGFR-TKI-resistant cells, enhanced YAP activity in inflammation, and the effect of the Hippo pathway on T cells, B cells, Tregs, macrophages, and myeloid-derived suppressor cells (MDSCs). These pleiotropic effects render the YAP and Hippo pathway a key pathway for exploitation in the future, in order to enhance our immunotherapy treatment strategies in oncology.
Highlights
Cancer immunotherapy has dramatically changed the clinical landscape of the treatment in many malignancies
Antibodies targeting PDL1 (Programmed death-ligand 1) and CTLA4 (Cytotoxic TLymphocyte Associated Protein 4) are important checkpoint inhibitors enhancing T cell killing of tumor cells, making them efficacious treatments in many solid tumors, such as lung cancer, melanoma, renal carcinoma, and others, while some types of solid tumors are resistant to immunotherapy
Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP, and TAZ) is significant for development and tissue homeostasis while defective signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer
Summary
Cancer immunotherapy has dramatically changed the clinical landscape of the treatment in many malignancies. Non-small cell lung cancer, melanoma, and renal cancer are examples where immunotherapy either alone or in combination with chemotherapy substantially improved overall survival. Even with these encouraging improvements, acquired resistance and disease progression is an issue, which needs to be solved. Antibodies targeting PDL1 (Programmed death-ligand 1) and CTLA4 (Cytotoxic TLymphocyte Associated Protein 4) are important checkpoint inhibitors enhancing T cell killing of tumor cells, making them efficacious treatments in many solid tumors, such as lung cancer, melanoma, renal carcinoma, and others, while some types of solid tumors are resistant to immunotherapy. Hippo pathway “key players”, such as YAP (yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are key drivers of wound healing, tissue regeneration, and tumor progression. Addressing and dissecting the key impact points of the Hippo pathway and YAP in the immune system will provide future challenges and perspectives in exploiting Hippo pathway blocking, in order to provide synergistic therapies with current immunotherapies by potentiating efficacy and overcoming resistance
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