Discovery of actionable drug targets to enhance T-cell infiltration and immune checkpoint blockade efficacy in pleural mesothelioma

Abstract

Background

Malignant pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. Although first-line nivolumab plus ipilimumab improves outcomes for some patients, a majority fail to respond. Mechanisms of immune resistance in PM remain poorly understood, underscoring the need for new clinically actionable drug targets to overcome immunotherapy resistance.

Methods

We established an in silico pipeline to investigate the molecular basis of T-cell exclusion in bulk RNA-sequencing data from 448 patients across three immune checkpoint blockade (ICB)-naïve PM cohorts. We assessed genome-wide correlations between gene expression and a previously validated cytotoxic T-cell signature score. Candidate immune evasion genes were prioritized based on clinical relevance, drug availability, and experimental feasibility for follow-up translational research.

Results

The in silico pipeline produced a highly reproducible catalogue of genes whose expression inversely correlates with T-cell infiltration, including established immune evasion factors (e.g. SOX4, KDM5B, CMTM4) and five novel FDA-approved drug targets (SMO, GANAB, ERBB2, GABRA1, ODC1). Seven additional targets (ARNT, BMPR1B, GSK3B, ACVR1, BACE1, RPS6KB1, ULK1) with preclinical inhibitors were also identified. Notably, we identified a possible link between primary cilia, Hedgehog signaling and T-cell exclusion. We found that SMO expression correlated with poor clinical response to second-line nivolumab plus ipilimumab in PM, highlighting SMO as a promising therapeutic target and potential biomarker for treatment resistance.

Conclusions

This comprehensive transcriptomic characterization of T-cell exclusion in PM reveals that targeting cilium-based Hedgehog signaling, in addition to multiple other actionable drug targets, could enhance the efficacy of ICB treatment in PM.