Neo-antigens offer promising therapeutic targets for immunotherapy of malignant pleural mesothelioma. The identification and targeting of neo-antigens was explored using pre-clinical models. Neo-antigen candidates from murine mesothelioma and lung cancer cell lines were predicted using a genomics-based bioinformatics approach. Between 14-317 cell line specific neoantigens were predicted across four cell lines. Up to 70% of tested candidates were found to be immunogenic but only one, UQCRC2, elicited an endogenous immune response. An additional neo-antigen, UNC45A, was 'unmasked' during effective immune checkpoint blockade (ICPB). The magnitude of pre-treatment responses to neo-antigen was correlated with therapeutic outcome.