Depletion of CD4+ CD25+ regulatory T cells promotes CCL21-mediated antitumor immunity.

Shuang Zhou,Zhiwei Zhen,Huihong Tao,Haixia Chen,Guolin Chen,Yaoqin Yang

doi:10.1371/journal.pone.0073952

Abstract

CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4+ CD25+ Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4+, CD8+ T cells and CD11c+ DCs within the tumor, coincident with marked induction of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.

Highlights

The induction of an effective antitumor immune response requires both antigen-presenting cells (APCs) and activated T cells
Our results suggested that CCL21-mediated antitumor immunity was strengthened when combined with anti-CD25 monoclonal antibodies (mAbs) administration, characterized by increasing the frequency of tumor-specific CD8+ T cells and CD11c+ dendritic cells (DCs), and enhancing the production of IL-12 and IFN-γ within the tumor, leading to improved antitumor efficacy
The results showed that CD4+ Foxp3+ Tregs gradually accumulated in the tumor tissue of early-stage hepatocellular carcinoma (HCC) on day 8 and 14 after Hepa1-6 sc inoculation (Figure 1A), CCR7 downregulation and Foxp3 upregulation in the development of HCC from day 8 to 29 were verified (Figure 1B)

Summary

Introduction

The induction of an effective antitumor immune response requires both antigen-presenting cells (APCs) and activated T cells. One might speculate that a stronger immune response could be achieved by attracting larger numbers of effector T cells and mature dendritic cells (DCs) to the tumor site. CCL21, formerly known as secondary lymphoid tissue chemokine (SLC), is a CC chemokine that is capable of recruiting DCs, naive T cells and B cells via its specific receptor CCR7 (CC chemokine receptor type 7) found on these cell types [3,4,5]. We and others have shown that vaccination with CCL21 modification is an effective strategy to stimulate antitumor immune responses in a mouse hepatocellular carcinoma (HCC) model [8,9,10,11]. The CCL21-mediated antitumor response is dependent on both

Methods

Results

Conclusion