Genomic <i>ERBB2</i>/<i>ERBB3</i> mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis.

Abstract

Patients with gallbladder carcinoma (GBC) lack effective treatment methods largely due to the inadequacy of both molecular characterisation and potential therapeutic targets. We previously uncovered a spectrum of genomic alterations and identified recurrent mutations in the ErbB pathway in GBC. Here, we aimed to study recurrent mutations of genes and pathways in a larger cohort of patients with GBC and investigate the potential mechanisms and clinical significance of these mutations. We performed whole-exome sequencing (WES) in 157 patients with GBC. Functional experiments were applied in GBC cell lines to explore the oncogenic roles of <i>ERBB2</i>/<i>ERBB3</i> hotspot mutations, their correlation with PD-L1 expression and the underlying mechanisms. ERBB inhibitors and a PD-L1 blocker were used to evaluate the anticancer activities in co-culture systems in vitro and in vivo. WES identified <i>ERBB2</i> and <i>ERBB3</i> mutations at a frequency of 7%-8% in the expanded cohort, and patients with <i>ERBB2</i>/<i>ERBB3</i> mutations exhibited poorer prognoses. A set of in vitro and in vivo experiments revealed increased proliferation/migration on <i>ERBB2</i>/<i>ERBB3</i> mutation. Ectopic expression of ERBB2/ERBB3 mutants upregulated PD-L1 expression in GBC cells, effectively suppressed normal T-cell-mediated cytotoxicity in vitro through activation of the PI3K/Akt signalling pathway and contributed to the growth and progression of GBC in vivo. Treatment with an ERBB2/ERBB3 inhibitor or a PD-L1 monoclonal antibody reversed these immunosuppressive effects, and combined therapy revealed promising therapeutic activities. <i>ERBB2</i>/<i>ERBB3</i> mutations may serve as useful biomarkers in identifying patients who are sensitive to ERBB2/ERBB3 inhibitors and PD-L1 monoclonal antibody treatment. NCT02442414;Pre-results.