Helle Sadam's research while affiliated with Tallinn University of Technology and other places

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Publications (1)

Top antibody response is individual-specific a–c The top antibody response was analyzed using cosine similarity indices (CSI) by comparing the composition and abundance values of the 2500 most IgG-bound peptides in each sample to that of the rest of the cohort in pairs (Supplementary Data 1). CSI values (range from 0 to 1, y-axis) between samples belonging to the indicated groups (x-axis) are depicted. Numbers above boxplots indicate the number of comparison pairs shown as dots. Comparisons of samples to themselves (CSI = 1) are not depicted. Comparisons between different individuals are indicated with circles while, comparison of the samples of the same patient are indicated with triangles. a Pairwise comparison between study groups and their matched controls. PEM-Mel – melanoma patients receiving pembrolizumab treatment (n = 5); CTRL-Mel – healthy controls for melanoma group (n = 80); MelVac – NSCLC patients who received MelCancerVac® vaccine (n = 6); MelVac-CTRL – paired samples of MelVac group taken before vaccination (n = 6); NSCLC – non-small cell lung cancer patients (n = 18); CTRL-NSCLC – non-cancer controls for NSCLC group (n = 10). b Pairwise comparisons of the 4 longitudinal samples of one NSCLC patient, who received 35 doses of MelCancerVac® and remained with stable disease (Supplementary Table 2), to the 4 samples themselves (MelVac1 vs MelVac1) and to the rest of the study cohort (n = 126 samples, MelVac1 vs Cohort). c Pairwise comparisons of pre- and post-vaccination immunoprofiles of vaccinated NSCLC patients (n = 6). MelVac Paired – comparison of pre- and post-vaccination samples of the same patient; MelVac Random - comparison of the pre-vaccination sample of one patient to the post-vaccination samples of all 5 other patients. Two-sided Wilcoxon Rank Sum test, **** p < 0.0001, p-values not adjusted for multiple comparisons.
The heterogeneity of antibody response converges on immunodominant epitopes Heatmaps depict differential antibody response to the 50 most immunodominant epitopes detected in pre- (Pre, n = 6) and post- (Vac, n = 6) vaccination samples of patients who received MelCancerVac® treatment (MelVac1-MelVac6). Rows depict immunodominant epitopes with numbers on the left of each panel referring to the specific epitope sequences provided in Supplementary Data 2. The number of epitopes differs for each patient as some epitopes were in the top 50 for both Pre and Vac samples, while some were detected in only one sample of the patient. Z-scores depict the abundance of IgG-binding peptides containing the immunodominant epitopes in each sample and are calculated separately for every patient by mean centering and autoscaling the abundance values across both Pre and Vac samples. Epitopes are ranked by highest-to-lowest abundance values as observed in the Vac sample. Z-score scale is cut-off at 97.5th percentile for better visualization of each panel.
Individual-specific immunoprofiles of antibody response to melanoma-associated antigens a Heatmap showing the antibody response to melanoma-antigens in patients with cancer and in the controls. Log10-transformation of the average abundance of the IgG-bound peptides containing epitopes with 100% identity to the indicated proteins are depicted. Value range ≤ 2.4 and ≥ 3.3 is provided for better visual representation. Group names of samples are depicted on the y-axis, individuals shown in numbers. x-axis indicates different melanoma-associated antigens (a total of 35 proteins) shown in Supplementary Table 3 and Supplementary Data 3. b, c Violin plots showing the average abundance of IgG-bound peptides containing epitopes with 100% identity to the specific proteins (shown above each graph, Supplementary Data 4) from panel a across study sub-cohorts. Two-sided Wilcoxon Rank Sum test, ns p > 0.5, *p < 0.05, **p < 0.01, *** p < 0.001, **** p < 0.0001, p-values not adjusted for multiple comparisons. CTRL-Mel – healthy controls for melanoma group (n = 21, all individuals older than 45 years); PEM-Mel – melanoma patients receiving pembrolizumab treatment (n = 5); MelVac-CTRL – paired samples of MelVac group taken before vaccination (n = 6); MelVac – NSCLC patients who received MelCancerVac® vaccine (n = 6); NSCLC – non-small cell lung cancer patients (n = 18).
Antibody response to 15 melanoma-specific epitopes is pre-existing before MelCancerVac® vaccination and boosted upon vaccine stimulation a Comparison of antibody response to 15 epitopes in samples taken before (n = 6, MelVac-CTRL) and after vaccination (n = 6, MelVac) in six MelCancerVac® receiving patients (MelVac1-MelVac6). x-axis denotes 15 epitopes as biomarkers (M1-M15), y-axis (Abundance ratio) shows the ratio of abundance values of IgG-bound peptides between paired MelVac and MelVac-CTRL samples of the patient (MelVaci[Mabundance + 1]/MelVac-CTRLi[Mabundance + 1], i – number of patient, M – biomarker) in base 10 logarithmic scale. Dashed line indicates ratio value 0 (1 in linear scale), i.e., where antibody reactivity to peptides containing the specific epitopes remained unchanged in MelCancerVac® post-vaccination cohort. Values > 0 indicate rise in seroreactivity after vaccination while <0 indicates decrease. Source abundance values for each epitope are presented in Supplementary Data 5. b Vaccine-dependent antibody response enhancement to the resolved epitopes was common. Data are shown for epitopes M4 and M5 by comparing abundances of IgG-bound peptides from the vaccinated patients, before (MelVac-CTRL) and after vaccination (MelVac). Abundance – number of IgG-bound peptides containing the specified epitope sequence detected in the sample. Two-tailed paired Wilcoxon Rank Sum test, * p < 0.05, p-values not adjusted for multiple comparisons. c Box plots show the abundance of IgG-bound peptides containing the specified epitopes (M1, M3, M9, M13, and M14) upon MVA competition analysis. MelVacComp – data from competition with DDM-1.7 melanoma cell lysate is shown. Relative abundance – the abundance of IgG-bound peptides containing the specified epitopes normalized to values of the paired vaccination-specific sample (MelVac) for each patient. d Box plots show the abundance of IgG-bound peptides containing sequences of the viral capsid antigen p18 (EBV VCA p18 epitope (161 GGQPHDTAPRGARKK 175) and the epitope of glycoprotein B (CMV gB; 70 ETIYNTTLKY 80)⁴⁰ from MVA competition analysis. MelVacComp – data from competition with DDM-1.7 melanoma cell lysate is shown. Abundance – the abundance of IgG-bound peptides containing the specified epitopes in base 10 logarithmic scale.
Antibody reactivity to epitopes of melanoma-antigens is associated with immunotherapy a Box plots showing the IgG response to peptides containing the 3 epitopes that were most differentiating for melanoma-specific immunotherapy as deemed by logistic regression model analysis. Abundance – number of IgG-bound peptides containing the epitope biomarker sequence detected in a sample. Control – healthy controls for melanoma group (CTRL-Mel, n = 80) and non-cancer controls of NSCLC group (CTRL-NSCLC, n = 10); MelVac – NSCLC patients who received MelCancerVac® vaccine (n = 6); PEM-Mel – melanoma patients receiving pembrolizumab treatment (n = 5). Two-sided Wilcoxon Rank Sum test **p < 0.01, *** p < 0.001, p-values not adjusted for multiple comparisons. b Logistic regression model of biomarkers M3, M9, and M11. AUC – area under curve; SE – standard error; CI – confidence interval.
Melanoma-specific antigen-associated antitumor antibody reactivity as an immune-related biomarker for targeted immunotherapies
  • Article
  • Full-text available

May 2022

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59 Reads

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5 Citations

Communications Medicine

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Mariliis Jaago

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Helle Sadam

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Background Immunotherapies, including cancer vaccines and immune checkpoint inhibitors have transformed the management of many cancers. However, a large number of patients show resistance to these immunotherapies and current research has provided limited findings for predicting response to precision immunotherapy treatments. Methods Here, we applied the next generation phage display mimotope variation analysis (MVA) to profile antibody response and dissect the role of humoral immunity in targeted cancer therapies, namely anti-tumor dendritic cell vaccine (MelCancerVac ® ) and immunotherapy with anti-PD-1 monoclonal antibodies (pembrolizumab). Results Analysis of the antibody immune response led to the characterization of epitopes that were linked to melanoma-associated and cancer-testis antigens (CTA) whose antibody response was induced upon MelCancerVac® treatments of lung cancer. Several of these epitopes aligned to antigens with strong immune response in patients with unresectable metastatic melanoma receiving anti-PD-1 therapy. Conclusions This study provides insights into the differences and similarities in tumor-specific immunogenicity related to targeted immune treatments. The antibody epitopes as biomarkers reflect melanoma-associated features of immune response, and also provide insights into the molecular pathways contributing to the pathogenesis of cancer. Concluding, antibody epitope response can be useful in predicting anti-cancer immunity elicited by immunotherapy.

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Citations (1)

... Interestingly, melanocyte-derived antigens like MLANA, TYR and PMEL are stably expressed across our selected UM samples. 20 Moreover, TMEM200C has been recently identified as a potential marker for progression in UM. 21 To further avoid peptide cross-reactivity, we first extracted all overlapping k-mer peptides of length 9-12 for all proteins expressed from the 22 prioritized genes. ...

Reference:

Gene network-based and ensemble modeling-based selection of tumor- associated antigens with a predicted low risk of tissue damage for targeted immunotherapy
Melanoma-specific antigen-associated antitumor antibody reactivity as an immune-related biomarker for targeted immunotherapies

Communications Medicine

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Mariliis Jaago

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Helle Sadam

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[...]

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