Immune checkpoint blockade (ICB) improves survival outcomes for patients with mesothelioma, however the mechanisms underpinning response remain elusive with only a minority of patients exhibiting response to ICB. Better understanding could facilitate therapeutic advances in both patient stratification and the rational treatment of relapse. The goal of this study was to gain greater insight into the cellular and molecular regulation of response to dual PDL1-VEGF inhibition (atezolizumab/bevacizumab) in patients with relapsed mesothelioma treated in the MiST4 single arm phase II trial (NCT03654833).
Diagnostic FFPE tumour blocks acquired from the MIST4 cohort, were subjected to RNA extraction and RNA sequencing(n=18) STAR and featureCounts were used for alignment and read counts Differential gene expression (DEseq2), gene set enrichment analysis (broadinstitute.org/gsea, Clusterprofile) were conducted pathway signatures scores for individual patient were calculated by single-sample GSEA. Immune microenvironment cells type deconvolution were deconvoluted using CIBERSORTx (https://cibersortx.stanford.edu/) and was compared with multiplex immunofluorescence as ground truth. Response was dichotomised into those patients exhibiting tumour growth (G) or reduction (R) measured by mRECIST1.1. Random forest machine learning, and non-parametric statistical testing was used to identify enriched transcriptional patterns in R (n=9) vs G (n=9) groups.
The G group exhibited significant enrichment of epithelial-mesenchymal transition (EMT) as estimated by GSEA compared with R. Conversely, inflammatory signatures were highly enriched in the R group versus G. Immune cell deconvolution revealed that NK cells are more abundant in R group (p value = 0.03). Chemokine analysis revealed a significant increase in CXCL12 (p = 0.039) and CXCL17 (p = 0.013) in R group.
EMT and inflammatory transcriptional signatures are exhibit reciprocal association with response to dual anti PDL1-VEGF therapy in relapsed mesothelioma. Further exploration is needed and ongoing to fully understand the genomic, immune microvironment and gut microbiome and their influence on these potentially predictive features.
University of Leicester.
Asthma and Lung UK.
A. Thomas: Other, Institutional, Expert Testimony: Bristol Myers Squibb; Other, Institutional, Speaker’s Bureau: Bristol Myers Squibb; Other, Institutional, Advisory Board: Bristol Myers Squibb. D.A. Fennell: Other, Institutional, Sponsor/Funding, Honoraria: Bayer; Boehringer Ingelheim; Bristol Myers Squibb; Inventiva Pharma; Novocure; RS Oncology; Targovax; Other, Institutional, Advisory Role: Bristol Myers Squibb; Inventiva Pharma; Novocure; Roche; Targovax; Other, Institutional, Speaker’s Bureau: Bristol Myers Squibb; Boehringer Ingelheim; Other, Institutional, Sponsor/Funding: Astex Pharmaceuticals; Bayer; Boehringer Ingelheim (Inst); Bristol Myers Squbb (Inst); Fuji Pharma (Inst); lab21 (Inst); Financial Interests, Institutional, Sponsor/Funding, Travel, Accommodations, Expenses: Bristol Myers Squibb; Janssen Oncology. All other authors have declared no conflicts of interest.