Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1+Antiangiogenesis in Malignant Pleural Mesothelioma

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

Automated summary

Recent research has shown that cancer immunotherapy combinations can improve the overall survival of advanced mesotheliomas, especially for patients who respond to the treatments. This study aimed to understand the biological factors that contribute to the primary resistance of mesotheliomas to immunotherapy and antiangiogenics. The combination of pembrolizumab and nintedanib was tested in thirty patients with advanced malignant pleural mesothelioma, and it was observed that refractory patients recruited cytotoxic T cells in their tumors but had high levels of somatic copy-number alterations and proinflammatory cytokines.