Genomic Instability and Pro-Tumoral Inflammation are associated with Primary Resistance to Anti-PD1 + Anti-Angiogenesis in Malignant Pleural Mesothelioma

Abstract Cancer immunotherapy combinations have recently 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 anti-angiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan anti-angiogenic tyrosine kinase inhibitor (TKI), in the multi-center 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 IL-6 and CXCL8. Those pro-inflammatory 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.