The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer

Abstract

The programmed death-ligand 1(PD-L1)/PD-1 pathway is an immunological checkpoint in cancer cells. The binding of PD-L1 and PD-1 promotes T-cell tolerance and helps tumor cells escape from host immunity. Immunotherapy targeting the PD-L1/PD-1 axis has been developed as an anti-cancer therapy and used in treating advanced human non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Yes-associated protein (YAP) is a key mediator of the Hippo/YAP signaling pathway, and plays important roles in promoting cancer development, drug resistance and metastasis in human NSCLC and MPM. YAP has been suggested as a new therapeutic target in NSCLC and MPM. The role of YAP in regulating tumor immunity such as PD-L1 expression has just begun to be explored, and the correlation between YAP-induced tumorigenesis and host anti-tumor immune responses is not well known. Here, we review recent studies investigating the correlation between YAP and PD-L1 and demonstrating the mechanism by which YAP regulates PD-L1 expression in human NSCLC and MPM. Future work should focus on the interactions between Hippo/YAP signaling pathways and the immune checkpoint PD-L1/PD-1 pathway. The development of new synergistic drugs for immune checkpoint PD-L1/PD-1 blockade in NSCLC and MPM is warranted.

Keywords: immunotherapy; malignant pleural mesothelioma (MPM); non-small cell lung cancer (NSCLC); programmed death-ligand 1 (PD-L1); yes-associated protein (YAP).

Figure 1

The mechanism of anti-programmed death-ligand 1(PD-L1)/PD-1 inhibitors in cancer therapy. In tumor cells, including non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), the binding of PD-L1 and PD-1 promotes T-cell tolerance and escape from host immunity. Immunotherapy targeting immune checkpoints for either anti-PD-1 or anti-PD-L1 has been developed and used in cancer therapy. Pembrolizumab and nivolumab are anti-PD-1 inhibitors, and atezolizumab and durvalumab are anti-PD-L1 inhibitors.

Figure 2

The regulation of the Hippo/YAP signaling pathway in malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). Hippo kinase, including NF2 and LATS1/LATS2, phosphorylate yes-associated protein (YAP) in the cytoplasm and lead to the degradation of YAP. In MPM, genetic mutations with loss of function in NF2, LATS1/LATS2, SAV1 and RASSF frequently occur, which leads to the degradation of YAP in the cytoplasm. Therefore, more YAP proteins translocate into the nucleus and activate transcription of downstream genes by forming complexes with transcriptional enhancer factors (TEAD), and promote tumorigenesis of MPM. In some NSCLC cells with high potential for drug resistance and metastasis, YAP expression increases at the protein level in the cytoplasm, and more YAP proteins translocate into the nucleus, which activates downstream genes including CTGF, cyr61 or other EGF expression genes, and then form autocrine loops to activate oncogenic pathways, such as MAPK signaling, which would inhibit the Hippo kinase. Therefore, the formation of these autocrine loops enhances YAP signaling, which promotes tumor cell proliferation, drug resistance and metastasis in NSCLC. Abbreviations: NF2, neurofibromatosis 2; LATS1, large tumor suppressor homolog 1; MST1, mammalian sterile-20 like kinase 1; SAV1, protein salvador homolog 1; RASSF, Ras-association domain family.

Figure 3

The regulation of programmed death-ligand 1 (PD-L1) expression by yes-associated protein (YAP) in human non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). We examined the PD-L1 enhancer region (−10,000 bps) upstream of the transcription starting site of PD-L1 and found 2 putative TEAD-binding sites (CATTCC), 7941 bps and 7911 bps upstream of the PD-L1 transcription start site. The results of chromatin immunoprecipitation (ChIP) assays in our previous two studies indicate that YAP regulates PD-L1 at the transcriptional level in the nucleus.