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

Significance

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.

 

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About the author

Ellen received her BSc with honours in Molecular Biology and Genetics at McMaster University in 2013. After graduation, she entered the combined Doctor of Medicine (MD)/Doctor of Philosophy (PhD) program in the Department of Pathology and Molecular Medicine at Queen’s University. During her PhD study, Ellen focuses on the roles of TAZ transcriptional co-activator in mammary tumorigenesis. She discovered that insulin receptor substrate 1 (IRS1) and PD-L1 as major downstream molecules mediating TAZ function in breast cancer progression and immune response. During her PhD study, she has published 9 international peer-review journal papers and won many awards such as the Frederick Banting and Charles Best Canada Graduate Scholarship Award and Gold Medal of Canadian Institute of Health Research (CIHR) National Student Research Poster Competition.

About the author

Dr. Yang is a Professor of Department of Pathology and Molecular Medicine, Queen’s University, Canada. Prof. Yang did his PhD in molecular biology at Memorial University of Newfoundland. Supported by a postdoctoral fellowship from Canadian Institute of Health Research (CIHR), Prof. Yang started his Post-Doctoral studies at Yale University School of Medicine in 1999. Upon completion of his Post-Doctoral training in 2004, Prof. Yang established his research lab at Queen’s University, and was appointed as a full-Professor in 2016.

Since starting his CIHR-supported postdoc in 1999 in the Department of Genetics at Yale University School of Medicine, Prof. Yang has focused on the role of the Hippo signalling pathway in cancer. He was the first scientist to work on the human homolog of Drosophila lats (LATS1), the founding member and core component of the Hippo pathway, in cancer. Since establishing his own research lab in 2004, he has done pioneering work on the role of the Hippo pathway in breast and lung cancer development, metastasis, immune response, and drug resistance. He has published 63 papers including 43 as first or senior authors in excellent biomedical journals such as Nat Cell Biol., Nat Commun, Cell Res., PNAS, Cancer Res., and Oncogene.

Dr. Yang’s research work is supported by the CIHR, Canadian Cancer Society, Canadian Breast Cancer Foundation, Cancer Research Society, and CQDM.

Reference

Janse van Rensburg, H.J. Azad, T., Ling, M., Hao, Y., Snetsinger, B., Khanal, P., Minassian, L.M., Graham, C.H., Rauh, M.J., and Yang, X. The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1, Cancer Research (2018), 78 (6), 1457-1470.

Go To Cancer Research (2018)

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