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Human inflammatory dendritic cells in malignant pleural effusions induce Th1 cell differentiation.

ABSTRACT: Dendritic cells are crucial for the initiation and regulation of immune responses against cancer and pathogens. DCs are heterogeneous and highly specialized antigen-presenting cells. Human DCs comprise several subsets with different phenotypes and functional properties. In the steady state, human DC subsets have been well studied. However, the components of DC subsets and their immune functions during the inflamed setting are poorly understood. We identified and characterized DC subsets in the malignant pleural effusions of NSCLC patients. We analyzed the capacity of these DC subsets to induce T-cell differentiation. We observed the presence of inflammatory DCs (infDCs) and macrophages in the malignant pleural effusions of NSCLC patients, as identified by the CD11C+HLA-DR+CD16-BDCA1+ and CD11C+HLA-DR+CD16+BDCA1- phenotypes, respectively. InfDCs represented approximately 1% of the total light-density cells in the pleural effusion and were characterized by the expression of CD206, CD14, CD11b, and CD1?, which were absent on blood DCs. InfDCs also expressed CD80, although at a low level. As infDCs did not express CD40, CD83 and CD275, they remained functionally immature. We found that TLR agonists promoted the maturation of infDCs. Compared with macrophages, infDCs had a weaker capacity to phagocytose necrotic tumor cell lysates. However, only infDCs induced autologous memory CD4+ T-cell differentiation into Th1 cells. For the first time, we found that infDCs were present in the malignant pleural effusions of NSCLC patients. We conclude that infDCs represent a distinct human DC subset and induce Th1 cell differentiation in the presence of TLR agonists.

SUBMITTER: Gu FF

PROVIDER: S-EPMC7183501 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Human inflammatory dendritic cells in malignant pleural effusions induce Th1 cell differentiation.

Gu Fei-Fei FF Wu Jing-Jing JJ Liu Yang-Yang YY Hu Yue Y Liang Jin-Yan JY Zhang Kai K Li Ming M Wang Yan Y Zhang Yong-An YA Liu Li L

Cancer immunology, immunotherapy : CII 20200212 5

Dendritic cells are crucial for the initiation and regulation of immune responses against cancer and pathogens. DCs are heterogeneous and highly specialized antigen-presenting cells. Human DCs comprise several subsets with different phenotypes and functional properties. In the steady state, human DC subsets have been well studied. However, the components of DC subsets and their immune functions during the inflamed setting are poorly understood. We identified and characterized DC subsets in the m ...[more]

PMID: 32052078

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Project description:A common symptom during late stage breast cancer disease is pleural effusion, which is related to poor prognosis. Malignant cells can be detected in pleural effusions indicating metastatic spread from the primary tumor site. Pleural effusions have been shown to be a useful source for studying metastasis and for isolating cells with putative cancer stem cell (CSC) properties. For the present study, pleural effusion aspirates from 17 metastatic breast cancer patients were processed to propagate CSCs in vitro. Patient-derived aspirates were cultured under sphere forming conditions and isolated primary cultures were further sorted for cancer stem cell subpopulations ALDH1+ and CD44+CD24-/low. Additionally, sphere forming efficiency of CSC and non-CSC subpopulations was determined. In order to genetically characterize the different tumor subpopulations, DNA was isolated from pleural effusions before and after cell sorting, and compared with corresponding DNA copy number profiles from primary tumors or bone metastasis using low-coverage whole genome sequencing (SCNA-seq). In general, unsorted cells had a higher potential to form spheres when compared to CSC subpopulations. In most cases, cell sorting did not yield sufficient cells for copy number analysis. A total of five from nine analyzed unsorted pleura samples (55%) showed aberrant copy number profiles similar to the respective primary tumor. However, most sorted subpopulations showed a balanced profile indicating an insufficient amount of tumor cells and low sensitivity of the sequencing method. Finally, we were able to establish a long term cell culture from one pleural effusion sample, which was characterized in detail. In conclusion, we confirm that pleural effusions are a suitable source for enrichment of putative CSC. However, sequencing based molecular characterization is impeded due to insufficient sensitivity along with a high number of normal contaminating cells, which are masking genetic alterations of rare cancer (stem) cells.

Project description:BackgroundPatients with malignant mesothelioma have a poor prognosis and only 40% respond to first line treatment; a combination of pemetrexed and cisplatin or carboplatin. We used primary malignant mesothelioma cells and an ex vivo chemosensitivity assay with future purpose to predict best choice of treatment. The clinical outcome of these patients might be predicted by measuring drug sensitivity.MethodsPleural effusions containing primary malignant mesothelioma cells were received from the diagnostic routine. We characterized and tested the chemosensitivity of 18 malignant samples and four benign samples from 16 different patients with pleural effusions. Cells were seeded in a 384-well plate for a robotized ex vivo testing of drug sensitivity to 32 different drugs. The primary cells were further characterized by immunocytochemistry to evaluate the proportion of malignant cells and to study the RRM1 and ERCC1 reactivity, two proteins associated with drug resistance.ResultsWe observed great individual variability in the drug sensitivity. Primary cell isolates were affected by between one and ten drugs, and resistant to the remaining tested drugs. Actinomycin D and daunorubicin were the two drugs effective in most cases. Adjusting efficiency of individual drugs for varying proportion of tumor cells and to the average effect on benign cells correlated with effect of pemetrexed, cisplatin and survival time. General drug sensitivity, proportion of malignant cells and reactivity to RRM1 correlated to each other and to survival time of the patients.ConclusionsThe proportion of malignant cells and RRM1 reactivity in the pleural effusions correlate to drug sensitivity and survival time. The variability in response to the commonly used chemotherapies emphasizes the need for tests that indicate best individual choice of cytotoxic drugs. The efficiency of the obtained results should preferably be corrected for admixture of benign cells and effects of given drugs on benign cells.

Dataset Information

Human inflammatory dendritic cells in malignant pleural effusions induce Th1 cell differentiation.

Publications

Human inflammatory dendritic cells in malignant pleural effusions induce Th1 cell differentiation.

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