Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma

Abstract

Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM. We characterized the landscape of potential neoantigens from SNVs identified in 27 MM patients and performed whole transcriptome sequencing of cell populations from 18 patient-matched pleural effusions. IFNγ ELISpot was performed to detect a CD8+ T cell responses to predicted neoantigens in one patient. We detected a median of 68 (range 7-258) predicted neoantigens across the samples. Wild-type non-binding to mutant binding predicted neoantigens increased risk of death in a model adjusting for age, sex, smoking status, histology and treatment (HR: 33.22, CI: 2.55-433.02, p = .007). Gene expression analysis indicated a dynamic immune environment within the pleural effusions. TCR clonotypes increased with predicted neoantigen burden. A strong activated CD8+ T-cell response was identified for a predicted neoantigen produced by a spontaneous mutation in the ROBO3 gene. Despite the challenges associated with the identification of bonafide neoantigens, there is growing evidence that these molecular changes can provide an actionable target for personalized therapeutics in difficult to treat cancers. Our findings support the existence of candidate neoantigens in MM despite the low mutation burden of the tumor, and may present improved treatment opportunities for patients.

Beyond Tumor Mutation Burden: Tumor Neoantigen Burden as a Biomarker for Immunotherapy and Other Types of Therapy

“…High TNB correlates with the abundance of TCR clonality and the infiltration of activated CD4 + and CD8 + T cells ( 50 , 67 ). This may be mediated by the elevated expression of chemokines induced by IFN-γ, such as chemokine (C-X-C motif) ligand (CXCL) 9, and by the recruitment of T cells or myeloid dendritic cells ( 45 , 68 , 69 ).…”

Pre-Clinical Research Advancements Relating to Improving the Diagnosis and Treatment of Malignant Pleural Mesothelioma: A Review

“…One recent study conducted by Sneddon et al utilised pleural effusion samples collected from 27 mesothelioma patients to screen and identify potential tumour cell-derived neoantigens. A median value of up to 68 different neoantigens was found to be responsive to CD8+ T cells, with a particularly strong CD8+ T cell response being detected for a predicted neoantigen produced by a spontaneous mutation in the ROBO3 gene [206]. This is just one example of a pre-clinical study that provides justified evidence that neoantigens represent promising actionable targets for the development of personalised MPM anti-tumour vaccines.…”

Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification

“…Different immune-related MPM phenotypes have already been described in recent studies using comprehensive approaches. [34-38] These studies use different techniques such as Nanostring™ technology,[35] mass cytometry,[34] or RNA-sequencing. [37] The diversity of obtained results suggests that the composition and role of the tumor microenvironment in MPM is remarkably complex and controversial, and thus further studies will contribute to elucidate this question.…”