Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis 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.

Inhibition of SUV39H1 reduces tumor angiogenesis via Notch1 in oral squamous cell carcinoma

“…Although advanced multimodal treatment strategies have improved prognosis and survival in patients with OSCC, the 5-year survival rate for patients with advanced OSCC remains around 50% ( Ren et al, 2020 ). In the process of cancer progression, tumor angiogenesis highly promotes tumor growth and metastasis, and inhibition of angiogenesis has long been a focus of tumor therapy research ( Danlos et al, 2023 ).…”

Towards inmunotherapeutic exploitation strategies of rotumor and antitumor cytokines

“…IL-6 expression in patients with advanced cancer has been associated with poor response to chemotherapy (223) and immunotherapy regimens based on immunecheckpoint inhibitor agents (195) and tyrosine kinase inhibitors (228). In patients suffering mesothelioma treated with ICIs, IL-6 transcription in the tumor and circulating levels are associated with poor response (229). It has also been found that IL-6 transcripts are linked to worse responses across clinical trials using PD-L1 blockade with atezolizumab (195).…”

“…Neutralization of IL-8 also improved the anti-tumor effect of docetaxel in a xenografted TNBC model and inhibited the establishment of metastatic niches, decreasing MDSCs and neutrophil recruitment and the expression of mesenchymal and stemness markers (246). In human cancer patients, circulating IL-8 strongly correlates with worse benefit from ICI immunotherapy in a manner related to neutrophil infiltrates ( 235) and together with IL-6 levels is associated with poor response to checkpoint inhibitors in mesothelioma patients (229).…”