CD25 and TGF-β blockade based on predictive integrated immune ratio inhibits tumor growth in pancreatic cancer

• Published in: Journal of translational medicine 2018-10, Vol.16 (1), p.294-294, Article 294
• Main Authors: Pu, Ning, Zhao, Guochao, Yin, Hanlin, Li, Jian-Ang, Nuerxiati, Abulimiti, Wang, Dansong, Xu, Xuefeng, Kuang, Tiantao, Jin, Dayong, Lou, Wenhui, Wu, Wenchuan
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animal models; Breast cancer; CD25 antigen; CD8 antigen; Clinical trials; Cytokines; Excretion; Flow cytometry; Foxp3 protein; Growth factors; Growth inhibition; Immunohistochemistry; Immunoregulation; Immunotherapy; Integrated immune ratio; Interleukin 10; Lymphocytes; Lymphocytes T; Medical prognosis; Multivariate analysis; Pancreatic cancer; Pancreatic ductal adenocarcinoma; PD-1 protein; Program death receptor-1; Regulatory T cell; Synergism; Tissues; γ-Interferon
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-018-1673-6

The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor due to the difficulty of disease diagnosis and therapy. Immunotherapy has had robust performance against several malignancies, including PDAC. In this study, we aim to analyze the expression of CD8 and FoxP3 on T lymphocytes and TGF-β expression in tumor tissues, and then analyze the possible clinical significance of these finding in order to find a novel effective immunotherapy target in PDAC using a murine model. A tissue microarray using patient PDAC samples was stained and analyzed for associations with clinicopathological characteristics. A preclinical murine model administrated with various immunotherapies were analyzed by growth inhibitor, flow cytometry, enzyme-linked immuno sorbent assay and immunohistochemistry. The infiltrating FoxP3 regulatory T cells (Tregs) in tumor tissues were associated with survival, while CD8 tumor infiltrating lymphocytes (TILs) were not. Considering the drawbacks of these measure alone, the number of CD8 and FoxP3 T cells were combined to create a new estimated value-integrated immune ratio (IIR), which showed excellent validity in survival risk stratification. IIR was further verified as an independent prognostic factor according to multivariate analysis as well as TGF-β expression. Association between TGF-β expression and infiltrating Tregs was also verified. Then, in our preclinical murine model, CD25 and TGF-β combination blockade had a higher tumor growth inhibitor value. This combination therapy significantly depleted periphery and intra-tumor FoxP3 Tregs while increasing intra-tumor CD8 TILs levels compared to controls or anti-TGF-β monotherapy (p