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Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer
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- Radestad, Emelie (författare)
- Karolinska Institutet
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- Klynning, Charlotte (författare)
- Karolinska Univ Hosp, Dept Gynecol Oncol, Stockholm, Sweden.
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- Stikvoort, Arwen (författare)
- Karolinska Institutet
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- Karolinska Institutet Karolinska Univ Hosp, Dept Gynecol Oncol, Stockholm, Sweden (creator_code:org_t)
- TAYLOR & FRANCIS INC, 2019
- 2019
- Engelska.
- Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 8:2
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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 coinhibitory 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-gamma, IL-2, TNF-alpha, IL-17 and CD107a. Blocking the PD-1 receptor resulted in significantly increased release of IFN-. 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Nyckelord
- Ovarian cancer
- tumor-infiltrating lymphocytes
- tumor-associated lymphocytes
- ascites
- checkpoint blockade
- PD-1 blockade
- co-inhibition
- PD-1
- TIM-3
- LAG-3
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- Uhlin, Michael
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