Comparative analysis of malignant pleural effusion and peripheral blood reveals unique T cell signatures associated with survival in mesothelioma patients.

Abstract

The success of cancer immunotherapies has highlighted the importance of monitoring the anti-tumour T cell response. Patients with mesothelioma frequently present with a malignant pleural effusion (MPE) that is commonly drained regularly to alleviate symptoms. As MPE contains tumour cells, T cells and cytokines, it provides a unique opportunity to sample immune events at the tumour site. However, there is minimal information on how MPE T cells are distinct from those in the blood, and whether T cell phenotypes unique to each compartment correlate with survival. We characterised T cell populations of matched MPE and blood from 31 mesothelioma patients using flow cytometry and bulk T cell receptor beta (TCRβ) sequencing. MPE CD8⁺ and CD4⁺ T cells displayed increased expression of PD-1, TIGIT, LAG-3 and TIM-3 compared to blood, with co-expression of inhibitory receptors greatest on MPE CD8⁺ T cells with a tissue resident memory T cell phenotype (CD69⁺CD103⁺). CD8⁺ TCRβ repertoires displayed clonal overlap between MPE and blood, suggesting that a majority of T cells traffic between these compartments. Finally, we show that high expression of PD-1 on circulating CD4⁺ T cells is an independent prognostic factor for poor survival in this patient group. This work suggests that MPE T cell phenotypes differ from those in circulation, with blood-based T cell subsets more sensitive predictors of outcome in this study.