Each malignant pleural mesothelioma (MPM) tumor site harbors different genetic mutations, and each one triggers a specific immune system’s response, according to a recent study by the University of Chicago’s Department of Medicine. Its findings offer valuable insight into the molecular mechanisms underlying MPM and may help design novel therapies to fight off cancer.
The study, “Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma” appeared in the journal OncoImmunology.
Cancer tissues are composed of various cell types with distinct molecular features. Knowing what differentiates one tumor from the other helps scientists design targeted and appropriate therapies for each cancer type. This particular study’s objective was to investigate the genetic heterogeneity in MPM tissues and their effect on the immune system’s response, as well as the relationships between mutations and the immune system in sub-regions of the tumors.
To do so, researchers carried out lab techniques that allow sequencing of the entire DNA of cancer cells and the identification of immune-related genes in samples from three different tumor sites (anterior, posterior, and diaphragm) obtained from six MPM patients. This “integrated analysis” allowed researchers to evaluate the distinct patterns of mutations and the immune signatures among MPM tumor samples and among the patients.
The team found that samples taken from different sites of the same tumor had different immune system responses. These depended on the mutations presented by cancer cells. Different mutations lead to the production of different molecules, the neoantigens, among cancer cells, and the immune system sends different cells to detect these molecules and fight off the respective cells.
Higher neoantigen production was linked to stronger expansion of T-cells (a type of immune cells) and a higher expression level of an immune-associated factor called PRF1, suggesting that novel cancer cell molecules trigger an increase in T-cell response that is specific for each tumor.
“Our integrated analysis of three different MPM tumor positions demonstrated a very high complexity in the context of intratumoral heterogeneity, as well as significant associations among mutation/neoantigen load, [expansion of T-cells], and expression levels of genes related to immune responses,” researchers concluded. “Our data also imply that identification of common [forms of T-cells], which may recognize common mutations across the different tumor sites including metastatic locations, might serve to improve therapeutic strategies, although obtaining biopsy samples from multiple sites remains challenging.”
