The Exploration Of Therapeutic Modalities And Predictive Biomarkers In Malignant Mesothelioma

Background:Malignant pleural mesothelioma(MPM)is characterized as an incredibly aggressive form of cancer with a dismal diagnosis and a dearth of specific biomarkers and therapeutic options.For MPM patients,the efficacy of immunotherapy may be influenced by damage-associated molecular pattern(DAMP)-induced immunogenic cell death(ICD).The objective of this work is to create a molecular profile associated with DAMPs to categorize MPM patients and predict their prognosis and response to immunotherapy.Methods:The RNA-seq of 397 patients(263 patients with clinical data,57.2%male,73.0%over 60 yrs.)were gathered from eight public datasets as training cohort to identify the DAMPs-associated subgroups of MPMs using K-means analysis.Three validation cohorts of patients or murine were established from TCGA and GEO databases.Comparisons were made across each subtype’s immune status,gene mutations,survival prognosis,and predicted response to therapy.Results:Based on the DAMPs gene expression,230 patients in the training cohort were categorized into subtype Ⅰ(inflammatory DAMPs subtype),which is distinguished by the enrichment of proinflammatory cytokine signaling,and 167 patients were classified into subtype Ⅱ(nuclear DAMPs subtype),which is classified by the upregulation of immune-suppressed pathways.In validation cohorts,the subtyping system was effectively verified.We further revealed a significantly higher frequency of copy number deletions in the nuclear DAMPs subtype.It was projected that the inflammatory DAMPs subtype enjoys a better prognosis and will respond to immunotherapy more favorably,suggesting that the developed clustering method may be implemented to predict the effectiveness of immunotherapy.Conclusions:We constructed a subtyping models based on ICD-associated DAMPs in MPM,which might serve as a signature to gauge the outcomes of immune checkpoint blockades.Our research may aid in the development of innovative immunomodulators as well as the advancement of precision immunotherapy for MPM.Background:Presently,second-line and beyond regimens for malignant mesothelioma are unsatisfactory.Vascular endothelial growth factor receptor tyrosine kinase inhibitors(VEGFR-TKIs)have been recommended as a standard of care in a variety of tumors,but have been poorly documented in malignant mesothelioma.This study retrospectively analyzed the clinical efficacy and factors of impact of VEGFR-TKIs in malignant mesothelioma.Methods:The clinical data of malignant mesothelioma patients treated with VEGFR-TKIs from April 1,2017 to March 16,2023 at Cancer Hospital of Chinese Academy of Medical Sciences were collected continuously.Statistical analysis was performed using R software and GraphPad Prism 8 software.Survival curves were plotted using the Kaplan-Meier method,and univariate and multivariate analyses of potential factors were performed by log-rank tests and Cox regression models.Restricted mean survival time analysis was used to explore the differences of factors on survival over time.Pearson correlation analysis was used to explore the relationship between PFS with prior receipt of bevacizumab and PFS with VEGFR-TKIs.P<0.05 was deemed to be statistically significant.Results:A total of 48 patients with malignant mesothelioma were included in this study,with a median follow-up time of 24 months(95%CI:18.5-56.3),and survival analysis showed a median progression-free survival(PFS)of 4.8 months(95%CI:2.9-8.8)and a median overall survival(OS)of 17.9 months(95%CI:13.5 months-NE).Of the 39 patients available for assessment of optimal outcome,6(15.3%)achieved partial response,20(51.3%)had stable disease,13(33.3%)had disease progression,and no patient achieved complete response.The results of log-rank test and COX regression analysis suggested that liver metastasis increased the risk of death and that primary site in the peritoneum and TKIs selection of apatinib were protective factors for progression-free survival.PFS of prior receipt of bevacizumab did not correlate with PFS of VEGFR-TKIs.A total of two patients discontinued treatments due to intolerable adverse effects.Conclusion:VEGFR-TKIs have shown promising efficacy in malignant mesothelioma with tolerable adverse effects.Liver metastasis is the risk factor of overall survival,while primary sites and choice of TKIs drug are factors of progression free survival.