Prognostic immunoinflammatory and transcriptomic profiles in patients with pleural mesothelioma undergoing immunotherapy.

AIM

A translational multiscale approach, encompassing tumor immune microenvironment (TIME), circulating immune-inflammatory benchmarks, and transcriptomic profiles, was undertaken to identify prognostic biomarkers of immunotherapy (IT) efficacy in patients with advanced pleural mesothelioma (PM).

METHODS

Advanced PM patients ( = 17) treated with nivolumab plus ipilimumab were prospectively enrolled in the FIL-QI 2021 study. Baseline blood and tumor samples were analyzed for immune subsets and functional markers (Granzyme B, Ki67) by flow cytometry, cytokines by multiplex ELISA, TILs and PD-L1 by immunohistochemistry, and gene expression by nanostring. Associations with overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), and modified disease control rate (mDCR) were assessed.

RESULTS

Higher baseline CD4 GnzB T cells were significantly associated with OS ≥ 12 months ( < 0.001), PFS ≥ 6 months ( = 0.027), and TTF ≥ 6 months ( = 0.016), along with lower CD14 monocytes (PFS:  = 0.038). Elevated proliferating CD8 Ki67 T cells (PFS:  = 0.038; TTF:  = 0.022) also predicted improved outcomes. Low IL-2 levels correlated with OS ≥ 12 months ( = 0.02). TIME analysis showed higher intratumor CD4 TILs ( = 0.03) and CD4/CD8 ratio ( = 0.016) in long survivors. Transcriptomics revealed nine genes differentially regulated according to clinical outcomes, among which emerged as a strong predictor of poor prognosis (LASSO-Cox regression model).

CONCLUSION

Parallel immune and transcriptomic profiling identifies biomarkers predictive of IT benefit in PM.