Association between effector-type regulatory T cells and immune checkpoint expression on CD8+ T cells in malignant ascites from epithelial ovarian cancer
Sho Sato, Hirokazu Matsushita, Daisuke Shintani, Yukari Kobayashi, Nao Fujieda, Akira Yabuno, Tadaaki Nishikawa, Keiichi Fujiwara, Kazuhiro Kakimi, Kosei Hasegawa
Abstract
Abstract Background Regulatory T cells (Tregs) play an important role in the antitumor immune response in epithelial ovarian cancer (EOC). To understand the immune-inhibitory networks of EOC, we addressed the association between Tregs and immune checkpoint expression on T cells in the tumor microenvironment of EOC. Methods A total of 41 patients with stage IIIC and IV EOC were included in the analysis. We harvested cells from malignant ascites and investigated them using multi-color flow cytometry. We categorized the Tregs into 3 groups: effector-type Tregs, naïve Tregs and non-Tregs, based on the expression patterns of CD45RA and Foxp3 in CD4 + T cells. Furthermore, the relationships between the expression of various immune checkpoint molecules, such as PD-1, on CD8 + T cells and each of the Treg subtypes was also evaluated. Results The median frequency of naïve Tregs, effector-type Tregs and non-Tregs were 0.2% (0–0.8), 2.0% (0–11.4) and 1.5% (0.1–6.3) in CD4 + T cells of malignant ascites from EOC patients, respectively. A high frequency of effector-type Tregs was associated with high-grade serous carcinoma compared with the other histotypes. Patients with higher proportions of effector-type Tregs showed a trend towards increased progression-free survival. We also demonstrated a correlation between a higher proportion of effector-type Tregs and increased PD-1 expression on CD8 + T cells. In addition, C–C chemokine receptor 4 expression was also observed in effector-type Tregs. Conclusion These data suggest that multiple immune-inhibitory networks exist in malignant ascites from EOC patients, suggesting an approach towards combinational immunotherapies for advanced EOC patients.