Researchers at Hiroshima University found that hyperactive YAP and TAZ proteins drive up PD-L2 to suppress T-cell attacks while simultaneously increasing genomic instability in cancer cells. Analysis of 1,662 patients showed Hippo pathway gene alterations were associated with higher mutational burden and improved overall survival following immune checkpoint inhibitor therapy, suggesting a mechanism for stratifying cancer patients.
YAP/TAZ hyperactivation mechanisms
- ▪Hiroshima University researchers found that YAP and TAZ increase PD-L2 expression through mechanisms involving TEAD, BRD4, and a super-enhancer in laboratory models.
- ▪A Hiroshima University study published in Communications Biology found that hyperactive YAP and TAZ proteins drive up PD-L2 expression while increasing genomic instability in cancer cells.
Hippo pathway regulation
- ▪When LATS1 and LATS2 regulators are lost, restraint on YAP and TAZ weakens, leading to increased YAP and TAZ activity in tumor cells.
- ▪The Hippo signaling pathway helps control cell growth by keeping YAP and TAZ protein activity in check through the regulators LATS1 and LATS2.
PD-L2 immune suppression
- ▪In head and neck squamous cell carcinoma laboratory experiments, removing PD-L2 made LATS1- and LATS2-deficient cells vulnerable to engineered EGFR-recognizing T-cell attacks.
- ▪PD-L2 binds to PD-1 receptors on CD8+ T cells to suppress T-cell attacks against cancer cells.
Genomic instability effects
- ▪Genomic instability and elevated DNA damage in cancer cells may increase their recognizability to CD8+ T cells.
- ▪Loss of LATS1 and LATS2 regulators in laboratory models was accompanied by increased YAP and TAZ activity, greater genomic instability, and elevated DNA damage in tumor cells.
Immunotherapy outcome predictors
- ▪The 1,662-patient analysis evaluated alterations in Hippo pathway genes including FAT1, NF2, LATS1, LATS2, and YAP1.
- ▪An analysis of 1,662 advanced cancer patients treated with immune checkpoint inhibitors showed that tumors with Hippo pathway alterations had better overall survival and higher mutational burden.
Head neck cancer treatment
- ▪Response rates to immune checkpoint inhibitor monotherapy remain below 20% in head and neck squamous cell carcinoma.
- ▪Anti-PD-1 antibodies used in head and neck squamous cell carcinoma block PD-1 receptors to prevent PD-L2 binding and restore T-cell activity.
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