Abstract
FoxP3+ regulatory T (Treg) cells have diverse functions in the suppression of antitumor immunity. We show that FoxP3hiCD45RA−CD4+ Treg cells [activated Treg (aTreg) cells] are the predominant cell population among tumor-infiltrating FoxP3+ T cells, and that high aTreg cell-infiltrating content is associated with reduced survival in patients with head and neck squamous cell carcinoma (HNSCC). In vitro studies have demonstrated that aTreg cells can suppress tumor-associated antigen (TAA) effector T cell immune responses in HNSCC. Moreover, C-C chemokine receptor 4 (CCR4) was specifically expressed by aTreg cells in the peripheral blood of HNSCC patients. Using a RayBiotech human chemokine antibody array, we showed that monocyte chemoattractant protein-1 (MCP-1), an endogenous CCR4-binding ligand, was specifically upregulated in the HNSCC microenvironment compared to the other four CCR4-binding ligands. Blocking MCP-1/CCR4 signaling-induced aTreg cell recruitment using a CCR4 antagonist evoked antitumor immunity in mice, and lead to inhibition of tumor growth and prolonged survival. Therefore, blocking aTreg cell trafficking in tumors using CCR4-binding agents may be an effective immunotherapy for HNSCC.
Highlights
Head and neck squamous cell cancer (HNSCC) is the sixth most common type of cancer [1]
We show that FoxP3hiCD45RA−CD4+ Treg cells [activated Treg cells] are the predominant cell population among tumor-infiltrating FoxP3+ T cells, and that high aTreg cell-infiltrating content is associated with reduced survival in patients with head and neck squamous cell carcinoma (HNSCC)
We found that the C-C chemokine receptor (CCR) 4 was predominantly expressed on aTreg cells compared to rTreg and nTreg cells, FoxP3–CD4+ T cell subsets, and other types of immune cells, indicating that chemokine receptor 4 (CCR4)-binding agents could be used to selectively block aTreg cell trafficking
Summary
Head and neck squamous cell cancer (HNSCC) is the sixth most common type of cancer [1]. Progression and recurrence of HNSCC and other malignancies are associated with severe immune dysfunction [3, 4]. Tumor-infiltrating FoxP3+CD25+CD4+ regulatory T (Treg) cells can promote local tumor growth through exerting immunosuppressive activities against tumor-associated antigen (TAA) T cell responses [3, 5,6,7,8,9,10,11]. Studies involving depletion of Tregs have shown that depletion of CD25+ T cells enhances antitumor immune responses [15, 16]. The apparent confusion regarding the role of Treg cells in suppressing antitumor immune responses might be explained as follows. Depletion of CD25+ T cells may reduce the number of activated CD4+ T cells [17]. We aimed to block Treg cell trafficking and accumulation in the tumor microenvironment, which could www.impactjournals.com/oncotarget provide an attractive therapeutic strategy against immune suppression
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