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BackgroundDespite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.MethodsWe generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.ResultsImmunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion ofCDKN2Awas highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome byCDK4/6inhibition, we tested whetherCDK4/6inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived fromCdkn2a(−/−)AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration ofCDK4/6inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 orCDK4/6inhibitor alone.ConclusionsWe identified a novel therapeutic target,CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials ofCDK4/6inhibitors in the more than 40% of patients with MPM who demonstrate loss ofCDKN2A.