Activation of PD-L1 by the Hippo pathway in cancer immune evasion

The dysregulation of important signaling pathways in malignant cells leads to the upregulation of genes that promote immune evasion. PD-L1 is a major protein that promotes immune evasion by tumor cells via the inhibition of T-cell activation, proliferation and interleukin-2 production, promotion of anergy and initiation of T-cell apoptosis. Although previous studies have focused on the development of PD-L1 blocking agents for the treatment of multiple cancers, the low response rates of the use of these therapeutic agents have established the need to gain a better understanding of the immunobiology of breast cancer and the cellular networks that affect the expression of PD-L1 in multiple cancers. Even though many studies have reported the major role of the Hippo pathway in the development of cancer, few of these have documented the role of YAP and its paralog TAZ, two core components of the Hippo pathway, in regulation of anticancer responses. Furthermore, there is a paucity of information on the relationship between Hippo signaling and the immune system and the effects of dysregulated Hippo signaling on the polarization of immune response against breast cancer.

Queen’s University scientists led by Professor Xiaolong Yang at the Department of Pathology and Molecular Medicine demonstrated the critical roles of the Hippo pathway in the modulation of the immune system and promotion of human cancer immune evasion.

The authors observed TAZ upregulated 25 immune-related genes and downregulated 34 immune-related genes while YAP upregulated 17 immune-related genes and downregulated 19 immune-related genes. TAZ and YAP induced the expression of PD-L1 at the protein level in MCF10A. Moreover, overexpression of YAP induced the expression of PD-L2 at the protein level.

The Canadian research team also found that the transient knockdown of MST1/2 or LATS1/2, major upstream inhibitors of YAP/TAZ in the Hippo pathway, in wild-type MCF10A mammary cells suppressed the inhibitory effect of YAP-S127 phosphorylation, enhanced the expression of PD-L1 at the protein and mRNA levels. In addition, overexpression of LATS2 in MDA-MB-231 breast cancer cells increased the phosphorylation of YAP-S127 and reduced the expression of PD-L1. Moreover, datasets from The Cancer Genome Atlas (TCGA) showed a correlation between the expression levels of TAZ and PDL-1 in multiple breast cell lines and lung cell lines (weak correlation) while fewer datasets from TCGA showed an association between YAP and PD-L1 mRNA expression.

Additionally, the authors reported that the knockout of TAZ decreased PD-L1 protein in Hs578T and MDA-MB-231 breast cancer cell lines. The overexpression of a TEAD-binding mutant form of TAZ (TAZ-S89A-F52/53A) in MCF10A and knockdown of TEAD transcription factor in MCF10A-TAZ-S89A also diminished the expression of PD-L1. Also, they discovered that the use of PD-L1 blocking antibody suppressed T-cell apoptosis induced by TAZ-S89A and the overexpression of TAZ-S89A suppressed IL2 production by T-cells in A549. Multiple genes were found to be differentially regulated by the TAZ constructs in human and mouse cells.

This novel study by Helena J. Janse van Rensburg (MD/PhD candidate) and her colleagues provides compelling evidence that the Hippo pathway and TAZ are major players in the promotion of human cancer immune evasion and multiple differences exist in the transcriptional regulation of PD-L1 expression in human and mouse cells. These findings will advance further studies on the roles of the Hippo pathway in the modulation of the immune system and promotion of human cancer immune evasion.