Tumor junction burden and antigen presentation as predictors of survival in mesothelioma treated with immune checkpoint inhibitors

Abstract Introduction The favorable outcomes with immunotherapy for mesothelioma were somewhat unexpected since this tumor has a low tumor mutation burden which has been associated with benefit in other cancers. Since chromosomal rearrangements are common in mesothelioma and have neoantigenic potential, we sought to determine whether they are associated with survival in patients treated with immunotherapy. Methods Pleural biopsies of mesothelioma after at least one line of therapy were obtained from patients (n=44) prior to treatment with nivolumab alone (NCT29908324) or in combination with ipilimumab (NCT30660511). RNA and whole genome sequencing were performed to identify the junctions resulting from chromosomal rearrangements, and antigen processing and presentation gene set expression. Associations with overall survival were estimated using cox models. An overall survival cutoff of 1.5 years was used to distinguish patients with and without durable benefit for use in receiving operating characteristic (ROC) curves. Results While tumor junction burdens were not predictive of overall survival, we identified significant interactions between the junction burdens and multiple antigen processing and presentation gene sets. The "regulation of antigen processing and presentation of peptide antigen" gene set demonstrated an interaction with tumor junction burden and was predictive of overall survival. This interaction also predicted 1.5-year or greater survival with an area under the ROC of 0.83. This interaction was not predictive of survival in a separate cohort of patients with mesothelioma who did not receive immune checkpoint inhibitors. Conclusions Analysis of structural variants and antigen presentation gene set expression may facilitate patient selection for immune checkpoint inhibitors.