Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intra-tumor heterogeneity over time.

Abstract

Background

Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and PD-L1 expression in naïve MPM cases and their change under chemotherapy.

Patients and methods

Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was performed. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival (OS).

Results

TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. 28 samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T-lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B-lymphocytes. Higher CD8+ T-lymphocytes, CD68+ macrophages and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki67). MPM cases characterized by higher CD8+ T- infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score (CS) including CD8+T-lymphocytes, necrosis, mitosis and proliferation index showed median OS of 11.3 months compared with 16.4 months in cases with high versus low CS (p<0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase of cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells.

Conclusions

TME enriched with cytotoxic T-lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopatological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.