Journal article
Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma
OncoImmunology, Vol.9(1), Art. 1684713
2019
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.
Details
- Title
- Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma
- Authors/Creators
- S. Sneddon (Author/Creator)C.M. Rive (Author/Creator)S. Ma (Author/Creator)I.M. Dick (Author/Creator)R.J.N. Allcock (Author/Creator)S.D. Brown (Author/Creator)R.A. Holt (Author/Creator)M. Watson (Author/Creator)S. Leary (Author/Creator)Y.C.G. Lee (Author/Creator)B.W.S. Robinson (Author/Creator)J. Creaney (Author/Creator)
- Publication Details
- OncoImmunology, Vol.9(1), Art. 1684713
- Publisher
- Taylor & Francis
- Identifiers
- 991005544942107891
- Copyright
- © 2019 The Author(s).
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.6 Immunology
- 1.6.214 Checkpoint Inhibition
- Web Of Science research areas
- Immunology
- Oncology
- ESI research areas
- Biology & Biochemistry