Spatially resolved, high-dimensional transcriptomics sorts out the evolution of biphasic malignant pleural mesothelioma: new paradigms for immunotherapy

Abstract

Background Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients’ management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place. Methods We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis. Results Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability. Conclusions Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease.

Single cell view of tumor microenvironment gradients in pleural mesothelioma

“…Consistent with this observation, CXCR3 (receptor for CXCL9/10/11) was more expressed in scS-high tumor T cells, especially in CD8 T cells and Tregs that have higher abundance in scS-high tumors. Further supporting this finding is a recent study employing spatial transcriptomics in PM biphasic samples, which showed increased lymphocytic infiltrate and expression of chemokines CXCL9/10 in sarcomatoid-enriched regions (58). Future time-course studies will be needed to decipher the precise molecular events that trigger these highly divergent TMEs that track with the sarcomatoid-epithelioid axis.…”

Pleural Mesothelioma: Treatable Traits of a Heterogeneous Disease

“…Within this framework, the work described provides fresh, pertinent viewpoints: it establishes for the first time the functional significance of the immune system and the inflammatory milieu in the mechanisms driving PM evolution; it also uncovers new information regarding the topography of the lesion and the communication circuits between immune cells and tumors, thereby offering new candidates to test as predictive biomarkers of ICI response. Furthermore, it suggests that M2-TAM polarization plays a crucial role in the development of immune evasion signals, identifying fresh possible targets [135].…”