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Published on: December 9, 2016
Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma
Yuichi Imai1,2,3, Kosei Hasegawa1,2, Hirokazu Matsushita4
1Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka-shi, Saitama 350-1298, Japan.
Abstract:
Expression of immune checkpoint molecules, including programmed cell death protein-1 (PD-1), has been reported on T cells in various types of cancer. However, the expression status of these molecules in the tumor microenvironment of epithelial ovarian cancer (EOC) has not yet been studied. A total of 54 cases of malignant ascites from patients with EOC were analyzed in the present study. The expression of PD-1, lymphocyte-activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and B and T lymphocyte attenuator (BTLA) on cluster of differentiation (CD)4+ and CD8+ T cells in malignant EOC ascites were investigated using multicolor flow cytometric analysis. The expression of PD-L1 in tumor cells, PD-L2 in HLA-DR-positive cells and galectin-9 in ascitic fluid was also analyzed. In addition, cytokine profiling of ascitic fluid was performed to understand the immune microenvironment of EOC. PD-1, LAG-3 TIM-3, and BTLA were expressed on 65.8, 10.6, 4.3 and 37.6% of CD4+ T cells, and on 57.7, 5.0, 4.9 and 15.7% of CD8+ T cells, respectively. Programmed cell death protein-1 (PD-1), LAG-3 and BTLA were more frequently expressed on CD4+ compared with CD8+ T cells. The co-expression of immune checkpoints was further investigated and results indicated that 39 (72.2%) and 37 patients (68.5%) expressed multiple immune checkpoints on CD4+ T cells and CD8+ T cells, respectively. In addition, lower levels of TNF-α and interleukin-6 in ascitic fluid were significantly associated with multiple immune checkpoint expression on CD8+ T cells. The present findings indicated that multiple immune checkpoint molecules were expressed on T cells in the EOC tumor microenvironment and the results may suggest the significance of simultaneous blockade of immune checkpoints to control EOC.
Insights
Immune checkpoint molecules like PD-1 are expressed on T cells in epithelial ovarian cancer (EOC) ascites. Multiple checkpoints were found on T cells, suggesting combined blockade may help control EOC.
Area of Science:
- Immunology
- Oncology
- Cancer Microenvironment Research
Background:
- Immune checkpoint molecules, such as programmed cell death protein-1 (PD-1), are expressed on T cells in various cancers.
- The expression status of immune checkpoints in the tumor microenvironment of epithelial ovarian cancer (EOC) remains understudied.
- Understanding immune cell dynamics in EOC ascites is crucial for developing effective immunotherapies.
Purpose of the Study:
- To investigate the expression of multiple immune checkpoint molecules on T cells within the malignant ascites of EOC patients.
- To analyze the co-expression patterns of these checkpoints on CD4+ and CD8+ T cells.
- To explore the relationship between cytokine profiles in ascites and immune checkpoint expression.
Main Methods:
- Analysis of malignant ascites from 54 EOC patients.
- Multicolor flow cytometry to assess expression of PD-1, LAG-3, TIM-3, and BTLA on CD4+ and CD8+ T cells.
- Analysis of PD-L1, PD-L2, and galectin-9 expression, alongside cytokine profiling (TNF-α, IL-6) of ascitic fluid.
Main Results:
- Significant expression of PD-1, LAG-3, TIM-3, and BTLA was detected on both CD4+ and CD8+ T cells in EOC ascites.
- Multiple immune checkpoints were co-expressed on a high percentage of both CD4+ (72.2%) and CD8+ (68.5%) T cells.
- Lower levels of TNF-α and IL-6 in ascites were associated with multiple immune checkpoint expression on CD8+ T cells.
Conclusions:
- Multiple immune checkpoint molecules are expressed on T cells within the EOC tumor microenvironment.
- The frequent co-expression suggests that targeting multiple checkpoints simultaneously may be a promising strategy for EOC treatment.
- These findings highlight the potential of combination immunotherapy in managing epithelial ovarian cancer.
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