Blockade of MCP-1/CCR4 signaling-induced recruitment of activated regulatory cells evokes an antitumor immune response in head and neck squamous cell carcinoma

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.

T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma

“…Consistently with this hypothesis the increased expression of Monocyte Chemotactic Protein-1 (MCP-1), C-C motif Chemokine Ligand 22 (CCL22), C-C chemokine receptors type 4 and 7 (CCR4 and CCR7), that are associated to a migratory phenotype, has been observed on HNSCC isolated Treg and in HNSCC tissue. 10,11,35,48 In addition, ligands for CCR4 and CCR7 were more expressed in HNSCC if compared with the adjacent healthy tissue. 10 In partial disagreement with the above-reported data, Sun and coworkers found high level of CCR7 C cells in the peripheral blood of HNSCC, but CCR7 expression was elevated in all T lymphocytes, irrespective of the subsets.…”

“…10 In partial disagreement with the above-reported data, Sun and coworkers found high level of CCR7 C cells in the peripheral blood of HNSCC, but CCR7 expression was elevated in all T lymphocytes, irrespective of the subsets. 48 Only the increased expression of CCR4 is a peculiar characteristic of Treg isolated from HNSCC patients. CCR4 expression is a marker of Treg activation as CCR4…”

“…49 The fundamental role of CCR4 in driving Treg migration toward tumor tissue has been further confirmed by experiments in mice, where blocking of MCP-1/CCR4 signaling came out in a lower frequency of Treg infiltrating the tumor and a significant inhibition of tumor growth. 48 Tumor-isolated Treg have a more immunosuppressive phenotype, with elevated expression of ectonucleotidase CD39, TGFb and CTLA-4. These cells are also more effective in inhibiting T cells proliferation in vitro than those isolated from peripheral blood, hence sustaining the activator effect of tumor microenvironment.…”

Dynamic changes in chemosensitivity immune predictors in patients with hypopharyngeal cancer treated with induction chemotherapy

“…However, tumors can escape from their host immune system in various ways, one of which is via regulatory T cells (Tregs) to suppress tumor‐specific T‐cell responses . This study and other studies have shown that host antitumor immune response could be effectively enhanced by depletion or functional inhibition of Tregs …”

CCL2 recruits T cells into the brain in a CCR2‐independent manner

“…In that study, CCR4 was predominantly expressed by activated regulatory T cells but not significantly expressed by CD8 T cells. Using a migration assay, it was shown that CCR4‐CCL2 signaling was involved in trafficking of activated regulatory T cells .…”