Development of mesothelioma-specific oncolytic immunotherapy enabled by immunopeptidomics of murine and human mesothelioma tumors
Nature Communications 2023 November 3 [Link]
Jacopo Chiaro, Gabriella Antignani, Sara Feola, Michaela Feodoroff, Beatriz Martins, Hanne Cojoc, Salvatore Russo, Manlio Fusciello, Firas Hamdan, Valentina Ferrari, Daniele Ciampi, Ilkka Ilonen, Jari Räsänen, Mikko Mäyränpää, Jukka Partanen, Satu Koskela, Jarno Honkanen, Jussi Halonen, Lukasz Kuryk, Maria Rescigno, Mikaela Grönholm, Rui M Branca, Janne Lehtiö, Vincenzo Cerullo
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. As the available therapeutic options show a lack of efficacy, novel therapeutic strategies are urgently needed. Given its T-cell infiltration, we hypothesized that MPM is a suitable target for therapeutic cancer vaccination. To date, research on mesothelioma has focused on the identification of molecular signatures to better classify and characterize the disease, and little is known about therapeutic targets that engage cytotoxic (CD8+) T cells. In this study we investigate the immunopeptidomic antigen-presented landscape of MPM in both murine (AB12 cell line) and human cell lines (H28, MSTO-211H, H2452, and JL1), as well as in patients’ primary tumors. Applying state-of-the-art immuno-affinity purification methodologies, we identify MHC I-restricted peptides presented on the surface of malignant cells. We characterize in vitro the immunogenicity profile of the eluted peptides using T cells from human healthy donors and cancer patients. Furthermore, we use the most promising peptides to formulate an oncolytic virus-based precision immunotherapy (PeptiCRAd) and test its efficacy in a mouse model of mesothelioma in female mice. Overall, we demonstrate that the use of immunopeptidomic analysis in combination with oncolytic immunotherapy represents a feasible and effective strategy to tackle untreatable tumors.
