Evaluating the effect of immune cells on the outcome of patients with mesothelioma

Abstract

Mesothelioma is a rare cancer usually affecting the pleura. It is characteristically associated with inhalation of asbestos fibres and accounts for 1% of cancers in the United Kingdom. Median survival remains poor at 4-18 months despite treatment.

Immunotherapy has established itself as an important treatment option in many solid tumours where survival benefit has been shown to be associated with CD8 infiltration. In mesothelioma, there are 3 small studies that suggest that CD8 infiltration may confer survival benefit.

Here, a systematic assessment was undertaken of the prognostic and predictive value of infiltrating adaptive and innate immune cells in a large cohort of patients with advanced mesothelioma. A tissue microarray from 302 samples was constructed. Markers of adaptive immune response CD4+ T helper and CD8+ Cytotoxic T cells, FOXP3+Tregs, CD45RO+Memory T cells and B-cells (CD20+), and innate immune response; macrophages (CD68+), natural killer cells (CD56+) and neutrophils (NP57+) were evaluated.

Surprisingly, CD8+ tumour infiltrating lymphocytes (TILs) did not predict for outcome. On multivariate analysis a high CD4+, high CD20+ and low NP57+ count were linked to better outcome in the epithelioid tumours. A low FOXP3+ predicted for good outcome in both epithelioid and non-epithelioid tumours.

Next, multiplex immunohistochemistry was utilised to further evaluate CD4+ and CD8+ T cell subtypes. This established the presence of MHC class II expression on epithelioid mesothelioma tumour cells and confirmed that some CD4+ T cell subsets (Tissue resident memory cells and T follicular helper cells), were associated with better outcome in epithelioid mesothelioma. The intriguing question of why CD4 + T cells function as the outcome determining immune effectors in mesothelioma, remains to be determined.

Mesothelioma-associated pleural fluid was evaluated to determine its utility as a surrogate for immune events in the solid tumour by transcriptomic analysis. T cells in the pleural fluid exhibited a phenotype characteristic of quiescent/naive cells.

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