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

Our plain-English summary of Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma, by S. Sneddon, C.M. Rive, S. Ma, et al (Oncoimmunology, 2020).

The study

• Authors: S. Sneddon, C.M. Rive, S. Ma, I.M. Dick, R.J.N. Allcock, S.D. Brown, R.A. Holt, M. Watson, S. Leary, Y.C.G. Lee, B.W.S. Robinson, J. Creaney
• Journal: Oncoimmunology
• Published: 2020;9(1):1684713
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.

In plain English

This laboratory study looked in malignant mesothelioma for neoantigens: altered protein pieces made by tumor mutations that the immune system might recognize. The authors used pleural effusion fluid from 27 patients in Western Australia, plus gene-activity data from the effusions of 18 of them. The article does not report asbestos-exposure data. Across samples, a median of 68 (range 7–258) neoantigens were predicted. Among 26 patients, having more neoantigens predicted to bind only in their mutated form was linked to a higher risk of death after adjusting for age, sex, smoking, tumor type and treatment (hazard ratio 33.22, 95% confidence interval 2.55–433.02). Before that adjustment the ratio was 0.38 (0.16–0.92). The authors cautioned that the higher risk appeared only after adjusting for tumor type and was likely skewed by a small number of non-epithelial tumors. In one patient, blood T cells grown in the laboratory reacted strongly to a mutated piece of the ROBO3 protein. The authors concluded they had identified a CD8+ T-cell response to a predicted neoantigen in a mesothelioma patient.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of patient samples: genetic sequencing of tumor cells and immune cells from pleural effusions, survival analysis, and immune (ELISpot) testing in one patient
• Who was studied: Pleural effusions from 27 malignant mesothelioma patients, median age at diagnosis 65 years (range 45–88). Gene-activity data came from 18 patient-matched effusions, and survival analysis used 26 patients. The study was approved in Perth, Western Australia. One patient (09567) was studied in depth.
• Exposure: The article does not report asbestos-exposure data. It states that patient demographics were detailed in an earlier publication. The study examined tumor mutations (single nucleotide variants), the neoantigens predicted from them, and immune cells in pleural fluid.
• Main results:
  • Across all patients' tumor cell samples, 2236 neoantigens were predicted, a median of 68 (range 7–258) per sample.
  • In the 26 patients in the survival analysis, a high versus low number of neoantigens predicted to bind in the mutated but not the normal state was associated with increased risk of death after adjustment for age, sex, smoking status, histology and treatment: hazard ratio 33.22 (95% CI 2.55–433.02), p = 0.007.
  • In the unadjusted (univariate) analysis, the same comparison gave a hazard ratio of 0.38 (95% CI 0.16–0.92), p = .03.
  • Patients with a high proportion of activated NK cells in their pleural effusions had better survival (log-rank p less than 0.01). High proportions of M0 or M1 macrophages were also linked to better survival.
  • Higher expression of the immune gene HLA-C was significantly associated with worse survival (log-rank p less than 0.01).
  • In the pleural effusion samples, 617 T-cell receptor sequences were detected (median 18 per sample, range 3–194). More detectable sequences correlated with a higher neoantigen burden (p less than 0.05).
  • In patient 09567, 41 mutations gave 67 predicted neoantigens, and 13 were tested. After laboratory expansion of blood T cells, the mutated ROBO3 peptide produced a strong IFN-γ response. The normal (wild-type) ROBO3 peptide produced no significant response. The responding cells were activated CD8+ T cells.
• The authors' conclusion: The authors concluded that they had identified a CD8+ T-cell response to a predicted neoantigen in a malignant mesothelioma patient and had characterized the predicted neoantigen landscape and tumor-immune interface in the pleural fluids of 27 patients. They suggested that pleural effusions could be used to identify such mutations and might lead to improved treatment opportunities.
• Limitations the authors state:
  • The link between more mutant-only binding neoantigens and death was seen only after adjusting for histology. The authors stated it was likely skewed by the small number of non-epithelial tumors, six of seven of which fell in the upper half of values.
  • The authors stated that the finding that low MHC class I gene expression was associated with longer survival could be due to the small sample size.
  • Neoantigens were predicted by computer. The predictions do not show whether the peptide is actually processed and presented by the tumor or recognized by T cells.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Immunotherapy, Pleural Effusion, Histology.

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