Pleural mesothelioma (PM) is a highly aggressive asbestos-related malignancy characterized by a 40-year latency period between exposure and diagnosis. Despite therapeutic advances, the 5-year survival rate remains around 10%. Dual immunotherapy (anti-PD-1 + anti-CTLA-4) has recently become a first-line treatment, benefiting mostly for the sarcomatoid subtype, which represents 20% of cases and historically carries the poorest prognosis. Its benefit for epithelioid patients remains less clear, particularly given the 30% risk of severe adverse events. The BioMAPS2 study, utilizing data from the IFCT-MAPS2 clinical trial, demonstrates that the sarcomatoid component exists as a transcriptomic continuum (S-score) that transcends traditional histology. Notably, this histomolecular assay identifies a subset of histological epithelioid patients with high S-scores who exhibit primary resistance to Nivolumab monotherapy, successfully overcome by the addition of Ipilimumab. Conversely, for epithelioid patients with low or absent sarcomatoid components, monotherapy yields comparable efficacy, suggesting that dual immunotherapy may be an unnecessary source of toxicity in this group.
Beyond tumor-intrinsic factors, the immune microenvironment (TME) significantly influences these therapeutic outcomes. BioMAPS2 identified a T-CD4-dominant, immunosuppressive TME where high macrophage infiltration correlates with poorer survival under monotherapy, independent of the S-score. To further characterize this, the ongoing MesoTAM study uses single-nucleus RNA sequencing (snRNA-Seq) to map the functional diversity of PM tumor-associated macrophages (TAM). Seven distinct TAM subpopulations were identified, mainly coming from monocyte infiltration rather than resident macrophages. They include those with antigen-presenting profiles (TREM2, PID1, CD14) and those associated with immunosuppression (RPS12, CD28, MARCO, and the transitional ENTPD1).
To model this heterogeneity, multicellular tumor spheroids (MCTS) were generated, showing that TAM polarization is driven by tumor-intrinsic signals rather than donor variability. Collectively, these findings support a new stratification model: reserving dual checkpoint inhibition for "molecularly sarcomatoid" or TAM-rich profiles, while prioritizing monotherapy for epithelioid patients with a favorable TME to optimize the benefit-risk ratio.

Guillaume Tosato is invited by the Paris Post-doc seminar series committee.