The immune system may recognise a cancer cell and still fail to destroy it.

Researchers at Hiroshima University and their international collaborators found that hyperactive YAP and TAZ (YAP/TAZ), two cancer-promoting proteins, were associated with genomic instability that may make cancer cells more recognisable to the immune system, while also increasing PD-L2, which helps the cells suppress T-cell attack.

That combination could matter for immune checkpoint inhibitor (ICI) therapy, which can block inhibitory signals that restrain T-cell activity.

If genomic instability makes a tumour more likely to be recognised by the immune system while PD-L2 helps suppress the T cells that recognise it, blocking such inhibitory signalling could leave the tumour more vulnerable to immune attack.

The researchers propose that this may help explain why tumours with certain Hippo pathway alterations were associated with better outcomes in a separate analysis of 1,662 patients treated with ICIs.

How YAP/TAZ helps cancer cells evade immune attack

The Hippo signalling pathway helps control cell growth by keeping YAP/TAZ activity in check, in part through the regulators LATS1 and LATS2 (LATS1/2).

When LATS1/2 are lost, that restraint can weaken, allowing YAP/TAZ activity to increase. Overactive YAP/TAZ are known to promote cancer growth, but their role in helping tumours evade immune attack has been less clear.

The researchers found that increased YAP/TAZ activity drove up PD-L2 expression. To test whether PD-L2 helped cancer cells resist immune attack, they exposed head and neck squamous cell carcinoma (HNSCC) cells to engineered T cells designed to recognise EGFR, a protein on the cancer cells.

Cells lacking LATS1/2 resisted the T-cell attack, but removing PD-L2 made them more vulnerable. The result indicated that PD-L2 contributed to their ability to evade attack by the engineered T cells.

The researchers also examined the other side of the apparent paradox. In laboratory models, loss of LATS1/2 was accompanied by increased YAP/TAZ activity, greater genomic instability, and more mutations in tumour cells.

Genome instability and elevated DNA damage may make cancer cells more likely to be recognised by CD8+ T cells.

Hippo pathway alterations linked to better immunotherapy outcomes

The study, published in Communications Biology, combined clinical and genomic data with experiments in cancer cells and mouse tumour models.

The patient dataset included several types of advanced cancer, while the laboratory experiments examined the mechanism across multiple cancer-cell types, with much of the detailed work focused on HNSCC.

In the patient analysis, tumours with alterations in selected Hippo pathway genes, including FAT1, NF2, LATS1, LATS2 and YAP1, were associated with better overall survival following ICI therapy than tumours without those alterations.

The altered tumours also carried significantly more mutations and had higher tumour mutational burden.

The researchers did not demonstrate that the laboratory-observed links among YAP/TAZ activation, genomic instability and PD-L2-mediated immune evasion caused the improved outcomes in those patients.

The clinical dataset contained genomic, tumour mutational burden and survival information but did not directly measure YAP/TAZ activation, PD-L2 expression and immune-cell infiltration in the same tumours.

“Cancer patients harbouring mutations regulating the Hippo pathway and YAP/TAZ hyperactivation may be sensitised to immune checkpoint inhibitor therapy owing to genome instability and PD-L2 expression,” said corresponding author Toshinori Ando, professor at Hiroshima University’s Graduate School of Biomedical and Health Sciences.

The authors said Hippo pathway alterations and associated YAP/TAZ hyperactivation may have potential as prognostic factors for stratifying patients undergoing ICI therapy.

However, further studies using independent patient cohorts with matched molecular and tumour microenvironment data are needed to translate the findings into clinical applications.

What the findings could mean for head and neck cancer

The findings may be particularly relevant to HNSCC, where response rates to ICI monotherapy remain below 20%.

Anti-PD-1 antibodies, a type of ICI already used to treat HNSCC, block PD-1, a receptor that acts as a brake on T cells when PD-L2 binds to it, helping restore T-cell activity.

Anti-PD-1 treatment itself was not tested in this study’s laboratory experiments. The team also investigated how YAP/TAZ increase PD-L2 expression.

Their experiments implicated TEAD and BRD4, along with a super-enhancer involved in regulating PD-L2.

Disrupting these components reduced YAP/TAZ-driven PD-L2 expression in laboratory models, pointing to possible therapeutic strategies that would require further testing.

The research team included Toshinori Ando, Nanako Kataoka, Yukina Kobayashi, Hisako Furusho and Mutsumi Miyauchi of Hiroshima University’s Department of Oral and Maxillofacial Pathobiology; Kento Okamoto, Yume Ueda, Kai Omachi, Yuga Maeda and Souichi Yanamoto of its Department of Oral Oncology; and Tetsuya Yoshimoto, Tomoaki Shintani and Mikihito Kajiya of the Centre of Oral Clinical Examination at Hiroshima University Hospital in Japan.

Kataoka and Kobayashi are also affiliated with the Centre of Oral Clinical Examination at Hiroshima University Hospital.

Other collaborators included Kuniaki Sato and J. Silvio Gutkind of the University of California, San Diego, in the United States; Yusuke Goto of Chiba University, Japan; Hiroki Izumi of the National Cancer Centre Hospital East, Japan; and Ramiro Iglesias-Bartolome of the National Cancer Institute at the U.S. National Institutes of Health.

Gutkind is also affiliated with UC San Diego’s Department of Pharmacology.

Article: Dysregulation of the Hippo pathway enhances PD-L2 transcription to promote immune evasion in head and neck squamous cell carcinoma

Source: Hiroshima University