Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer
| Autor: | Michael Uhlin, Ole Mogensen, Emelie Rådestad, Arwen Stikvoort, Charlotte Klynning, Silvia Nava, Isabelle Magalhaes |
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| Přispěvatelé: | Hematology laboratory, AII - Cancer immunology, CCA - Cancer biology and immunology |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy lag-3 Immunology lcsh:RC254-282 tumor-associated lymphocytes 03 medical and health sciences Ovarian tumor ascites 0302 clinical medicine Immune system co-inhibition medicine tim-3 Immunology and Allergy Receptor Original Research Tumor-infiltrating lymphocytes business.industry pd-1 Cancer medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology ovarian cancer Oncology 030220 oncology & carcinogenesis tumor-infiltrating lymphocytes Cancer research checkpoint blockade Ovarian cancer business lcsh:RC581-607 pd-1 blockade Ex vivo CD8 |
| Zdroj: | OncoImmunology, 8(2). Landes Bioscience OncoImmunology, Vol 8, Iss 2 (2019) Rådestad, E, Klynning, C, Stikvoort, A, Mogensen, O, Nava, S, Magalhaes, I & Uhlin, M 2019, ' Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer ', OncoImmunology, vol. 8, no. 2 . https://doi.org/10.1080/2162402X.2018.1535730 Oncoimmunology |
| ISSN: | 2162-4011 |
| DOI: | 10.1080/2162402X.2018.1535730 |
| Popis: | Suppression of immune reactivity by increased expression of co-inhibitory receptors has been discussed as a major reason as to why the immune system fails to control tumor development. Elucidating the co-inhibitory expression pattern of tumor-infiltrating lymphocytes in different cancer types will help to develop future treatment strategies. We characterized markers reflecting and affecting T-cell functionality by flow cytometry on lymphocytes isolated from blood, ascites and tumor from advanced ovarian cancer patients (n = 35). Significantly higher proportions of CD4+ and CD8+ T-cells expressed co-inhibitory receptors LAG-3, PD-1 and TIM-3 in tumor and ascites compared to blood. Co-expression was predominantly observed among intratumoral CD8+ T-cells and the most common combination was PD-1 and TIM-3. Analysis of 26 soluble factors revealed highest concentrations of IP-10 and MCP-1 in both ascites and tumor. Correlating these results with clinical outcome revealed the proportion of CD8+ T-cells without expression of LAG-3, PD-1 and TIM-3 to be beneficial for overall survival. In total we identified eight immune-related risk factors associated with reduced survival. Ex vivo activation showed tumor-derived CD4+ and CD8+ T-cells to be functionally active, assessed by the production of IFN-γ, IL-2, TNF-α, IL-17 and CD107a. Blocking the PD-1 receptor resulted in significantly increased release of IFN-γ suggesting potential reinvigoration. The ovarian tumor environment exhibits an inflammatory milieu with abundant presence of infiltrating immune cells expressing inhibitory checkpoints. Importantly, we found subsets of CD8+ T-cells with double and triple expression of co-inhibitory receptors, supporting the need for multiple checkpoint-targeting agents to overcome T-cell dysfunction in ovarian cancer. |
| Databáze: | OpenAIRE |
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