Lung cancer (Amsterdam, Netherlands) · 2025
Discovery of actionable drug targets to enhance T-cell infiltration and immune checkpoint blockade efficacy in pleural mesothelioma.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Genugten Jasper H L T van, Faulkner Daniel, Hahne Jens C, Poile Charlotte, Wessels Lodewyk, Fennell Dean A, Baas Paul
Аннотация
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.
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.