Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study

Abstract

Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches.

Single cell view of tumor microenvironment gradients in pleural mesothelioma

“…Indeed, TOX2 has been shown to be essential for maintaining a T FH phenotype in ex vivo GC T FH isolated from human tonsils (45). Supporting our finding, TLSs have been previously observed in PM using bulk-RNA and histological analysis on a cohort of 123 chemo-naive patients, which was linked to improved survival and enriched in epithelioid tumors (57). Finally, we identified a CXCL9/10/11 expressing TAM population in PM that is associated with high scS-score samples and likely contributes to chemotaxis for T cell trafficking to the tumor core.…”

“…To investigate a link between TLS presence and molecular subtypes, we correlated expression of GC T FH marker TOX2 with the top markers of GC B cells (Figure 5J) and found significant association only in epithelioid samples (Figure 5K; r = 0.46, P value = 0.0004). Interestingly, a previous study showed histological evidence of TLS presence in a subset of epithelioid PM tumors associated with longer survival (46).…”

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations

“…Patients’ biopsies used for transcriptional profiles comparison were collected during the MATCH (Mesothelioma And Translational Clinical and Health) study [ 30 ], an observational biological study for the identification of biomolecular markers of MPM, their relationship with survival and tumor response in a retrospective clinical cohort, and their evaluation in a prospective cohort of consecutive patients with newly diagnosed MPM.…”

Immunotherapy of mesothelioma: the evolving change of a long-standing therapeutic dream

“…More recently, lymphoid aggregates or tertiary lymphoid structures (TLS) have been identified in PM microenvironment, suggesting their potential prognostic role. Along this line, Mannarino and collegues, in a retrospective multicenter cohort of 129 chemo-naive epithelioid PM patients, demonstrated that long-term survivors (>36 months) had a specific inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations compared to short survivors (<12 months) ( 43 ). These findings further underline that PM patients, even within the same histological subtype, can have a very different clinical outcome, and demonstrate that the TME and its multiple cellular components can play a role in the clinical course of PM.…”