Role of evaluating tumor‑infiltrating lymphocytes, programmed death‑1 ligand 1 and mismatch repair proteins expression in malignant mesothelioma

Abstract

The tumor immune microenvironment (TME) and immune checkpoints have been reported to serve a role in the pathogenesis of malignant mesothelioma (MM) and treatment outcome. Additionally, mismatch Repair (MMR) deficiency appears to enhance the response to checkpoints blockade in several tumors. The aim of the present study was to analyze programmed death-1 ligand 1 (PD-L1) expression in MM and to characterize the TME. This could help to understand the immune response, and evaluate its prognostic and predictive values. We also investigated MMR protein expression. We retrospectively analyzed 55 mesotheliomas to determine PD-L1, CD4 + , CD8 + , mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and PMS1 homolog 2, mismatch repair system component (PMS2) expression. We used an immunoscore (1+, 2+ and 3+) to evaluate tumor-infiltrating lymphocytes (TILs). TILs were observed in all but two samples (53/55); the majority had an immunoscore 1+ (30/53), while 2+/3+ was reported for 23/53 samples. A predominance of CD8 + was highlighted in 8 cases (15%). PD-L1 expression of ≥1% on tumor cells was displayed in 40 cases; in 9 of these, ≥50% expression was reported. Of note, alterations in MMR staining was not observed. In addition, survival analysis revealed that epithelioid subtype was associated with better prognosis. We observed a trend towards poorer prognosis for ≥50% PD-L1 expression on tumor cells, lower immunoscore (1+) and CD8 + TIL predominance. The present study highlighted the importance of exploring the TME and the standardization of PD-L1 assessment guidelines to apply in the field of immunotherapy.

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…In the recently published PROMISE-MESO trial, 48.9% of the patient had less than 1% PD-L1 expression, 28.2% had 1-20% and 18.5% more than 20% PD-L1 expression ( 96 ). Another study described 73% to be positive (> 1%) and 27% negative (<1%) ( 97 ). Inaguma et al.…”

Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

“…Across all histologic subtypes, however, an increasing balance of M2 macrophages relative to lymphocyte infiltration has been shown to be predictive of shorter survival (16,20). Among lymphocytes, an increased proportion of CD8 relative to CD4 T cells has been associated with shorter survival (16,24,25). However, this effect was found to be reversed following neoadjuvant chemotherapy in one early study (26).…”

“…In general, MPM displays an immunosuppressive microenvironment mediated by M2 macrophages and characterized by high lymphocyte infiltration (Table 1) (15,25). This immunosuppressive phenotype is more common in non-epithelioid MPM (20) and as a result the degree of overall macrophage infiltration has been associated with shorter survival in non-epithelioid MPM alone (14,15).…”

“…Investigations of the effect of checkpoint molecule expression, including PD-L1, are also ongoing. Studies have shown that higher PD-L1 expression is associated with shorter survival (25). Non-epithelioid tumors exhibit higher PD-L1 expression than epithelioid tumors (23), and there is substantial transcriptomic variability among the expression of checkpoint molecules along the epithelial-to-mesenchymal spectrum observed in a large series of MPM transcriptomes (51).…”

“…In addition to their effect on the TIL composition, the relative composition of the lymphoid infiltrate itself was found to be an independent predictor of outcomes. The balance between CD4 and CD8 T cells is key in this respect (24,25). Fusco and collaborators (24) analyzed 88 MPM tumors.…”