Inhibition of Transforming Growth Factor-β–Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types

Abstract

Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-β (TGF-β), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-β-mediated immunosuppression in DLNs and examined whether local inhibition of TGF-β augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-β-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-β type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-β suppressed the proliferation of regulatory T cells and increased the number of tumor antigenspecific CD4 + or CD8 + cells producing IFN-γ. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-β-mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model pro-vides a novel rationale for molecular cancer therapeutics targeting TGF-β. [Cancer Res 2009;69(12):5142-50]

TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression

“…Anti-TGF-β antibody treatment also reverses the suppressive function of Tregs [30]. In the E.G7 tumor model, the effect of TGF-β inhibition was clearly shown in draining lymph nodes, in which suppression of Treg proliferation and an increase in the number of tumor antigen-specific CD4+ or CD8+ cells producing IFN-gamma was found [83]. However, one should note that while TGF-β is known to play a crucial role in CD4+Foxp3+ Treg cell induction, there are few reports to show that the improved immune responses from TGF-β antagonism is mediated by CD4 Treg cells ([79] and personal communication with Dr Lalage Wakefield).…”

Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity

“…At present, several studies have focused on the therapeutic potential of antagonizing the TGFß pathway against cancer (12,13). The most advanced TGFß signaling antagonist in clinical development is large-molecule including monoclonal antibodies (14)(15)(16). During this decade, many small molecules to inhibit TGFß type I receptor have been developed.…”

Transforming growth factor-β1 29T>C genetic polymorphism is associated with lymph node metastasis in patients with adenocarcinoma of the lung

“…In addition, Fujita et al showed that inhibition of TGF-β suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4 + and CD8 + cells producing IFN-γ in mouse lymph nodes [11]. Taken together, these findings suggest that TGF-β suppresses antitumor immune responses within lymph nodes.…”

“…In these patients, moreover, production of TGF-β is often upregulated not only in the tumor cells but also in the stromal cells surrounding the tumor [9]. The paracrine TGF-β produced by these cells stimulates angiogenesis, suppresses immune responses [10,11], and increases the interaction of tumor cells with the extracellular matrix, leading to greater invasiveness [12].…”