Abstract
BackgroundThe 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.MethodsA 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.ResultsThe 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 < 0.05). Anti-CD25 monotherapy alone also had the ability to deplete periphery and intra-tumor Tregs (p < 0.05). The excretion of intra-tumor IL-10, TGF-β was notably lower but higher IFN-γ excretion in this combination immunotherapy. Such combination immunotherapy was further confirmed to synergize with anti-PD-1 monotherapy to improve tumor growth inhibition and cure rates.ConclusionsThe combination of CD25, TGF-β and PD-1 blockade plays a potentially effective role in inhibiting tumor formation and progression. Our results also provide a strong rational strategy for use of IIR in future immunotherapy clinical trials.
Highlights
The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor due to the difficulty of disease diagnosis and therapy
At low (40×) and high (400×) magnification, CD8 was located on T cell membranes, while Foxp3 was distributed in the T cells nucleus
CD8 was highly expressed in 43.3% (39/90) of PDAC samples, forkhead boxP3 (FoxP3) was highly expressed in 48.9% (44/90), while transfer growth factor beta (TGF-β) in 44.4% (40/90)
Summary
The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor due to the difficulty of disease diagnosis and therapy. We aim to analyze the expression of CD8 and FoxP3 on T lymphocytes and TGF-β expression in tumor tissues, and analyze the possible clinical significance of these finding in order to find a novel effective immunotherapy target in PDAC using a murine model. With the burgeoning trend of immunotherapy, many malignances are receiving good experimental and clinical efficacy with this novel therapy, including PDAC [4, 5]. PDAC has some unique characteristics including the existence of a dense stroma and tumor microenvironment full of immunosuppressive mediators. These unique characteristics made these tumors a dynamic entity both in terms of immune response and a solid barrier to drug penetration. The problem remains finding targets that are appropriate for Tregs interference and enhancement of C D8+ TILs, which is critical to the efficacy of immunotherapy
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