Tumor-derived transforming growth factor-β is critical for tumor progression and evasion from immune surveillance.

Zheng Li,Li-Juan Zhang,Li-Qing Zhao,Zi-Yu Meng,Hong-Ru Zhang,Gao-Fei Tian,Zheng-Hu Jia,Zhen-Zhou Wu,Zhi-Nan Yin,Xiao-Li Mao,Jun Tian

doi:10.7314/apjcp.2014.15.13.5181

Abstract

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-β(TGF-β) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-β produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-β in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-β using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ Treg cells, and consequently enhanced IFN-γ production by CTLs. Knockdown of tumor-derived TGF-β also significantly reduced the conversion of naive CD4+ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-β suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-β is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-β may serve as a potential therapeutic approach for cancer.

Highlights

Intact immune responses, such as immune surveillance, are required for suppressing tumor development and progression, and tumors often create an immunosuppressive microenvironment that can facilitate tumor growth and block antitumor immune responses through producing soluble factors, such as cytokines, which in turn recruiting other regulatory cells
Our study provided evidence that tumor-derived TGF-β is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-β may serve as a potential therapeutic approach for cancer
Establishment of TGF-β knockdown B16 cells To knockdown tumor-derived TGF-β in B16 cells, four plasmids designed to express shRNA targeting mouse TGF-β1 and negative control plasmid coding for a scramble shRNA were transfected into B16 cells respectively, and the transfection efficiency was monitored by the Emerald green fluorescent protein (EmGFP) reporter within these plasmids (Figure 1a)

Summary

Introduction

Intact immune responses, such as immune surveillance, are required for suppressing tumor development and progression, and tumors often create an immunosuppressive microenvironment that can facilitate tumor growth and block antitumor immune responses through producing soluble factors, such as cytokines, which in turn recruiting other regulatory cells. Tumor-derived TGF-β regulates the number of CD4+Foxp3+ Treg cells and MDSCs in tumor microenvironment and CD8+ T cell function in spleen and tumor To define the underline mechanisms by which tumorderived TGF-β mediates the immune suppression, tumor tissues as well as spleens from mice subcutaneously injected with two kinds of B16 cells were collected for the analysis of the percentage of CD4+Foxp3+ Treg cells and MDSCs. about 24% of TILs were found to be MDSCs in the mice bearing negative control B16 cells, whereas only approximately 9% in the mice bearing TGF-β knockdown B16 cells.

Results

Conclusion