Buffy Coat Immunotranscriptomics for Diagnosis of Malignant Pleural Mesothelioma

Abstract

Malignant pleural mesothelioma is a highly aggressive tumor primarily caused by asbestos exposure and associated with poor clinical outcomes. The availability of a robust non-invasive test for the screening of asbestos-exposed subjects is therefore an important unmet clinical need. It is widely recognized that the immune system can play a fundamental role in the control of tumor growth within an organism. Simultaneously, the presence of cancer cells can activate different immune cells to undergo various phenotypic and functional changes. Buffy coat—a novel circulating microenvironment of leukocytes and platelets—may thus reflect critical immuno-oncologic activity, pathways, and molecular programs. We hypothesized the immunotranscriptome of circulating buffy coat could accurately distinguish malignant pleural mesothelioma from high-risk asbestos exposure. Buffy coat RNA was extracted from 84 patients having resection: 40 patients with malignant pleural mesothelioma and 44 patients with asbestos exposure. Gene expression profiling was performed using a Pan Cancer Immune Panel for 770 immune genes and cytokines, and significantly different genes between cohorts were selected to develop diagnostic models. Using 1000 loops of cross validation, a 37 gene signature separated malignant pleural mesothelioma from asbestos exposure with a mean validation AUCS of 0.925. Our buffy coat immunotranscriptomic signature is at least comparable to the most commonly used blood-based diagnostic biomarker for MPM, serum mesothelin-related peptide. In addition, immunophenotyping and pathway analysis of differentially expressed genes characterized MPM buffy coat as a relatively tumorigenic and immunosuppressive state. Several of the most differentially expressed genes encode proteins implicated in cancer development (e.g., CD63, CD44, ISG15, CD59, IL1R2, and TAPBP) and may hold clinical value as therapeutic targets. Larger studies on externally validated cohorts are needed to refine the signature for clinical relevance and develop a more robust diagnostic panel.