Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic cancer that derives from the mesothelial cells of the pleura and is causally associated with exposure to asbestos. Because of the poor specificity of the clinical symptoms, when it is diagnosed, malignant cells, which are extremely resistant to therapies, have already spread throughout the pleural layers, leading to a poor outcome. Although the recent approval of the combination immunotherapy with anti-CTLA-4 and anti-PD-1 represents a breakthrough for MPM, many patients are still refractory or relapsed after a few months of therapy. Therefore, there is an urgent need of reliable biomarkers to improve patient selection for immune checkpoint blockades (ICBs), as well as of new therapeutic strategies to boost antitumor immunity. Recent insights into these unmet medical needs are discussed in this Research Topic. Specifically, Perrino et al. review the clinical efficacy and the most promising predictive biomarkers of response to ICBs in MPM. In addition to widely recognized determinants -such as PD-L1 expression and tumor mutational burden (TMB) -and specific prognostic factors for MPM (i.e. histological subtype), they discuss new elements, which definitively warrant to be further investigated and prospectively validated. Particularly, it is worth noting that in spite of the low TMB, MPM cells usually show multiple chromosomal rearrangements, which can lead to the expression of neo-antigens, thereby predicting response to ICBs.

Besides histological classification in epithelioid, sarcomatoid and biphasic MPM, a growing number of studies have pointed out a striking molecular heterogeneity, which suggests the existence of a range of molecular phenotypes associated with different responsiveness to ICBs and outcome. Based on these premises, the studies of Yang et al. and Liu et al. generate in-silico classification systems for MPM, which could be exploitable Frontiers in Immunology frontiersin.org 01