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Dijana Djureinovic
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.13 - Scavenger Receptor MARCO Defines a Targetable Tumor-Associated Macrophage Subset in Lung Cancer (ID 8641)
15:45 - 17:30 | Author(s): Dijana Djureinovic
- Abstract
- Presentation
Background:
Tumor-associated macrophages (TAMs) with immunosuppressive and tumor promoting features are attractive targets for immunotherapy. MARCO is a scavenger receptor expressed on a subpopulation of macrophages in secondary lymphoid organs. A recent study performed in animal models concluded that treatment with an anti-MARCO antibody results in reprogramming of the TAMs and inhibition of tumor growth and metastatic spread. The expression and function of MARCO in lung cancer TAMs is not known.
Method:
The infiltration of TAMs expressing MARCO, CD68, CD163 and MSR1, in the tumor and stromal compartments, was analyzed by immunohistochemistry in a non-small cell lung cancer (NSCLC) cohort (n=352). In addition, PD-L1 expression was assessed on tumor cells. Immunofluorescence was performed on selected cases to evaluate marker co-expression. Associations to immune cells and regulatory inflammatory pathways were studied in a subset of cases (n=174) with available RNA-seq data.
Result:
A large variance in TAM density could be observed between cases as well as a strong correlation between CD68 and CD163, indicating a pro-tumor phenotype of infiltrating macrophages. Correlation to clinical data showed a trend towards worse survival for patients with high macrophage infiltration. TAM expression of MARCO was seen on a subpopulation of pro-tumor macrophages. The majority of MARCO expressing TAMs were found to be located within tumor cell nests. Interestingly, stromal macrophages expressing MARCO tended to aggregate in close proximity to the tumor nests. On the transcriptomic level, increased MARCO gene expression correlated to genes linked to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules like PD-L1 and CTLA-4. The association between macrophage infiltration and tumor cell PD-L1 expression was confirmed by immunohistochemistry. Also, co-expression of PD-L1 and MARCO could be detected on certain macrophages within the tumor cell nests.
Conclusion:
MARCO expression characterizes a specific subpopulation of pro-tumor macrophages that are enriched in PD-L1 positive NSCLC cases. Patients with significant infiltration of MARCO positive TAMs could benefit from treatment with anti-MARCO antibodies, possibly in combination with available immune checkpoint inhibitors.
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.01 - Cancer Testis Antigens and Mutational Load in Relation to the Immune Landscape of Non-Small Cell Lung Cancer (ID 9369)
15:45 - 17:30 | Author(s): Dijana Djureinovic
- Abstract
- Presentation
Background:
The avoidance of immune surveillance by tumor cells is an accepted hallmark of cancer. The aim of this study was to describe the natural immune landscape of NSCLC tissue, to identify important regulatory associations and potential targets of immune response. This includes mutational load and cancer testis antigen (CTA) expression, and the comprehensive analysis of tumor infiltrating immune cells in connection with immune signaling and clinical information.
Method:
Tissue microarrays including duplicate cancer samples of 357 NSCLC patients were stained with antibodies against CD3, CD4, CD8, CD45RO, FoxP3, CD20, CD138, and CD44 to analyze the protein expression in the stroma and tumor compartment. For 197 of these cases, corresponding RNA-seq data were available. The immunological data were correlated to the transcriptomic data and to patients’ clinical outcome. The mutation status and the mutational load was based on a targeted next-generation sequencing panel of 82 genes (HaloPlex).
Result:
The immune cell infiltration was predominantly in the stroma, although CD8 and FoxP3 cells also showed relevant infiltration of the tumor cell compartment. The amount of T-cells of different subsets and CD20-positive B-cells correlated positively to each other. A higher mutational load was associated with higher CD8 T-cell infiltrates, CD45RO cells, FoxP3 regulatory cells as well as CD20-positive B-cells in the tumor compartment. In contrast, the number of expressed CTAs were associated with an abundance of CD45RO-positive cells in the stromal compartment. Only CD44-positivity (HR = 0.61, p< 0.01) as well as high CD20 positive B-cells (HR = 0.34, p< 0.01) and plasma cell (CD138, HR = 0.71, p< 0.05) counts in the tumor, and for plasma cells also the stromal (HR = 0.61, p< 0.01), compartment were associated with longer overall survival.
Conclusion:
Here we describe natural immune profiles in a large clinical NSCLC patient cohort. Interestingly both mutational load and CTA expression is associated with the abundance of distinct immune cell infiltrates. We could not confirm the impact of tumor infiltrating T-cells on survival. However, the consistent prognostic impact of both B-cell markers indicates a major role of the humoral immune response in lung cancer.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-020 - Autoantibody Profiles of Cancer-Testis Genes in Non-Small Cell Lung Cancer (ID 9330)
09:30 - 16:00 | Presenting Author(s): Dijana Djureinovic
- Abstract
Background:
Cancer testis (CT) genes are expressed in various types of cancer but otherwise restricted to normal tissues of testis and placenta. Several CT genes have shown to encode immunogenic proteins that are able to induce an anti-tumour response in cancer patients. The presence of autoantibodies towards expressed CT proteins could indicate which CT proteins that are more suitable for immunotherapeutic interventions, as these are recognized by the patient´s immune system.
Method:
Suspension bead arrays (Luminex) were used to analyse the presence of autoantibodies towards expressed CT proteins in plasma samples from patients with non-small cell lung cancer (NSCLC). The technology enables to screen for autoantibodies in minute amount of patient plasma. Protein fragments with an average length of 80 amino acids, produced within the Human Protein Atlas, were coupled to unique beads, allowing multiplex analysis of 244 different autoantibodies towards antigens representing 198 unique genes in each sample. The primary sample set included 51 samples from 34 individuals taken before radiation therapy and 17 samples taken after radiation therapy. Longitudinal plasma samples taken during radiation therapy were available for most individuals resulting in a total of 89 samples.
Result:
Of 198 analysed CT genes, autoantibodies against antigens representing 25 genes were detected in at least one of the 51 samples from the primary study set. The autoantibody detection ranged from five different autoantibodies in two individuals to no detected autoantibodies in seven individuals. Among those individuals with samples available both before and after radiation therapy (n=13), the autoantibody profiles were not altered by the treatment. Three individuals however showed autoantibodies towards one additional protein in the sample taken after radiation therapy compared to the sample before radiation. In two individuals, autoantibodies detected towards one protein in the sample taken before radiation were not detected in the sample taken after radiation. Unsupervised hierarchical clustering with 25 detected autoantibodies and all 89 samples showed that samples from the same individual cluster based on the autoantibodies´ profile. There was no apparent association of autoantibody profiles with clinical parameters (histology, gender, age, stage). However, patients with detected autoantibodies showed a longer overall survival than patients without autoantibodies.
Conclusion:
This study provides a first comprehensive analysis of autoantibody detection against antigens representing 198 CT genes. Among the identified autoantibodies only AKAP4 has been reported previously in NSCLC. The individual autoantibody profiles showed only minor differences between samples taken before, during and after radiation therapy.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-066 - Identification of Crucial Gene Targets in the in Situ Environment of Cancer by Google Network Ranking (ID 10151)
09:30 - 16:00 | Author(s): Dijana Djureinovic
- Abstract
Background:
The vast majority of cancer driver genes in non-small cell lung cancer (NSCLC) are characterized by activating mutations or high gene copy number amplifications. To identify tumorigenic genes without any genomic aberrations remains difficult. Network analysis of gene expression provides the possibility to describe the relations of genes to each other and by that to estimate their importance.
Method:
To analyze gene networks of NSCLC we applied the PageRank algorithm that was established by Google primarily to order the importance of websites. Data from NSCLC cancer tissue (n=1002) and normal lung (n=110) were retrieved from the cancer genome atlas (TCGA) and the highest expressed genes (n=16000) were ranked according to their importance in normal lung tissue as well as in NSCLC tissue. Subsequently, the difference in rank between normal and cancer was analyzed. Four comparative categories were defined and were analyzed with respect to their cellular function (GO annotation) and survival. Additionally, organ specific (n=163), housekeeping (n=68) and lung cancer related genes (n=62) were compared in the networks.
Result:
Genes with the highest importance (top 100) in normal lung tissue were connected with cellular metabolic processes or membrane transport. In cancer, most genes (top 100) were related to cell cycle and mitosis, chromosomal localization and DNA processing. There was no overlap between the two lists. Organ specific genes increased in average in their rank (p<0.001) while housekeeping genes decreased (p<0.001). Notably, cancer related genes did not significantly change their relevance in the network. Among the genes (top 100) that increased rank from normal to cancer, many were related to antigen processing and presentation.
Conclusion:
The PageRank algorithm provides the possibility to unbiasedly evaluate the importance of genes in the gene expression network of cancer. Surprisingly, not traditional cancer related genes but several hitherto not recognized genes were identified to be of regulatory importance and may be target for therapy. Once again, our results indicate the significance of the immune response in changes related to cancer.
