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

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.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1673-6) contains supplementary material, which is available to authorized users.

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer

“…Infiltrating FoxP3+ regulatory T cells (Tregs) in tumor tissues are considered a major obstacle to clinical efficacy of tumor immunotherapy and associated with a poor prognosis. 44 45 The ability of galunisertib to block the suppressive activity of human Tregs has been demonstrated in vitro 46 but has not yet been observed clinically. Additional studies examining tumor microenvironment characteristics may be warranted to increase the efficiency of PD-1 immunotherapy and improve the prognosis of pancreatic cancer.…”

Independent effect of postoperative neutrophil-to-lymphocyte ratio on the survival of pancreatic ductal adenocarcinoma with open distal pancreatosplenectomy and its nomogram-based prediction

“…The blood parameters reflect the anti-factor and promoting-factor of inflammatory response and immune response to the cancer 16 . Our previous study had investigated the changes of microenvironment in PDAC, which showed the prognosis-related changes of regulatory T cells and CD8 + T cells 22 . Our present research indicated that elevated poNLR was an independent predictive factor to the prognosis of PDAC undergoing ODPS.…”

Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

“…Similarly, an increased number of IFN-γ+CD8+ T cells are also an indicator of the successful combination treatment of bintrafusp alfa and radiotherapy [ 150 ]. Pu et al have identified an integrated immune ratio based on the number of infiltrating CD8+ T cells and FOXP3+ Tregs to predict tumour suppression in the combination immunotherapy of CD25, TGF-β, and PD-1 blockade [ 174 ]. In melanoma, the treatment mediated by TGFBR1 inhibitor SB505124 in the presence of IL-12 overexpression demonstrates enhanced immune responses, and NK1.1 is a potential biomarker for increased effector cells and enhanced cancer-killing effects [ 175 ].…”