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Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Patrick Micke)
Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Solna, Sweden.
Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Solna, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Cancer testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. 

To comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against CT47A genes, PAGE3, VCX, MAGEB1, LIN28B and C12orf54 were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.

In conclusion, we identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.

Keywords [en]
Lung cancer, adenocarcinoma, squamous cell cancer, cancer immunity, tumor markers, MAGE, PAGE
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-347809OAI: oai:DiVA.org:uu-347809DiVA, id: diva2:1195948
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2018-04-11
In thesis
1. Transcriptomic and Proteomic Analysis of Tumor Markers in Tissue and Blood from Patients with Lung Cancer
Open this publication in new window or tab >>Transcriptomic and Proteomic Analysis of Tumor Markers in Tissue and Blood from Patients with Lung Cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite recent treatment advancements, the survival outcome remains poor for the majority of patients with non-small cell lung cancer (NSCLC). The aim of this thesis was to evaluate protein expression to predict prognosis and identify biomarkers that can be used as targets for immunotherapy or for early detection of NSCLC.

In Paper I an optimized immunohistochemistry (IHC)-based prognostic model was developed for NSCLC. The prognostic performance of the model was compared to the clinicopathological parameters that are used in the clinical setting to predict outcome. The protein model failed to outperform clinicopathological parameters in predicting survival outcome questioning the potential of IHC-based assessment of prognostic markers in NSCLC.

In Paper II the human testis-specific proteome was profiled using RNA-sequencing (RNA-seq) data from testis and 26 other organs. More than 1000 genes demonstrated a testis-enriched expression pattern which makes testis the tissue with the most tissue-specific genes. The majority of the testis-enriched genes were previously poorly described and were further profiled by IHC. This analysis provides a starting point to increase the molecular understanding of testicular biology.

In Paper III the profiling of cancer-testis antigens (CTAs) was performed in NSCLC by using RNA-seq data from 32 normal organs and NSCLC. Ninety genes showed CTA expression profiles. The transcriptomic data were validated by IHC for several CTAs. The comprehensive analysis of CTAs can guide biomarker studies or help to identify targets for immunotherapeutic strategies.

In Paper IV the reactivity of CTAs was evaluated by measuring the abundance of autoantibodies in plasma from patients with NSCLC and benign lung diseases. Twenty-nine CTAs demonstrated exclusive reactivity in NSCLC and six of them were reactive in an independent NSCLC cohort. These findings suggest that some CTAs are immunogenic and could be utilized in immunotherapy.

In Paper V an immunoassay was used on lung adenocarcinoma plasma samples and samples from benign lung diseases. The plasma levels of 92 cancer related proteins were used to build a model that discriminated lung adenocarcinoma from benign controls with a sensitivity of 93% and a specificity of 64%. The results indicate that this assay is promising for the early detection of NSCLC.

In summary, this thesis presents an integrative analysis of lung cancer tissue and blood samples to characterize NSCLC on the transcriptomic and proteomic level and to identify cancer specific proteins.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 52
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1463
Keywords
non-small cell lung cancer, prognostic biomarkers, cancer-testis antigens, prediction model, tumor markers, autoantibodies, testis, screening
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-348349 (URN)978-91-513-0328-4 (ISBN)
Public defence
2018-06-08, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
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Supervisors
Available from: 2018-05-09 Created: 2018-04-11 Last updated: 2018-10-08

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