Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome

Abstract

Immunohistochemical analysis of FOXP3 in primary breast tumors showed that a high number of tumor-infiltrating regulatory T cells (Ti-Treg) within lymphoid infiltrates surrounding the tumor was predictive of relapse and death, in contrast to those present within the tumor bed. + , and CD8 + T cells was documented within lymphoid infiltrates. Altogether, these results show that Treg are selectively recruited within lymphoid infiltrates and activated by mature DC likely through TAA presentation, resulting in the prevention of effector T-cell activation, immune escape, and ultimately tumor progression. This study sheds new light on Treg physiology and validates CCR4/CCL22 and ICOS as therapeutic targets in breast tumors, which represent a major health problem.

Human FOXP3 and cancer

“…Most human tumors are infiltrated by Treg, presenting as small cells, with lymphocytic morphology, and high FOXP3 labeling in their nucleus (Table 1). FOXP3 þ cells were sometimes localized in the vicinity of tumor cells, but rather predominant in the peripheral lymphoid-enriched areas (Curiel et al, 2004;Mizukami et al, 2008;Gobert et al, 2009). The density of FOXP3 þ cells was reported to be significantly higher in malignant than in normal tissue (Bates et al, 2006;Hiraoka et al, 2006;Miller et al, 2006;Mizukami et al, 2008).…”

“…(1) Treg from the thymus, lymph nodes, bone marrow and peripheral blood express CC-chemokine receptor 4 (CCR4) and can be attracted by the abundant expression of CC-chemokine ligand 22 (CCL22, a CCR4 ligand) produced by cancer cells and tumor-infiltrating macrophages (Curiel et al, 2004;Miller et al, 2006;Mizukami et al, 2008;Gobert et al, 2009). (2) Even if Treg are refractory to proliferation when activated by antibodies against CD3 and CD28 in vitro, they could proliferate actively when located in the tumor stroma, probably under the effect of IL-2 released in the tumor microenvironment and TCR activation by dendritic cells recognizing tumorspecific antigens (Gobert et al, 2009). In experimental tumor models, we demonstrated that a subset of immature myeloid dendritic cells was recruited in the tumor and induced an active proliferation of Treg through TGF-b expression (Ghiringhelli et al, 2005).…”

“…Meanwhile, another team administered metronomic low dose oral cyclophosphamide for patients with hormone-resistant prostate cancer. (Gobert et al, 2009) 191 Unfavorable Colorectal carcinoma (Salama et al, 2009) 967 Favorable Cervix carcinoma (Jordanova et al, 2008) 115 Unfavorable Esophagus carcinoma (Yoshioka et al, 2008) 122 Not significant Gastric carcinoma (Mizukami et al, 2008) 80 Unfavorable (*) Head & neck carcinoma (Badoual et al, 2006) 84 Favorable Hepatocellular carcinoma (Gao et al, 2007) 302 Unfavorable Kidney carcinoma (Siddiqui et al, 2007) 170 Not significant Lymphoma (B cell) (Carreras et al, 2006) 98 Favorable Lymphoma (Hodgkin) (Alvaro et al, 2005) 257 Favorable Ovary carcinoma (Curiel et al, 2004) 104 Unfavorable Pancreatic carcinoma (Hiraoka et al, 2006) 198 Unfavorable…”

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

“…7,8 Elevated levels of CCL22 have been described in many human tumors, including B-CLL, Hodgkin lymphoma, breast, lung and gastrointestinal cancers. [9][10][11][12][13][14] For many of these tumors, elevated intratumoral CCL22 concentrations are associated with a higher tumor infiltration by Treg. Treg are an inhibitory subset of T helper cells, whose function is to suppress cytotoxic T effector cell functions, [15][16][17] involving cell-contact dependent and cell-contact independent mechanisms such as consumption of IL-2, expression of the cellsurface antigen CTLA-4 and secretion of inhibitory cytokines such as TGF-b and IL-10.…”

Marginal zone CD169+macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance

“…In particular, CCL22 is a prominent chemotactic agent driving Treg accumulation in tumors, and antagonism of either CCL22 or its receptor (CCR4) has potent antitumor effects (18)(19)(20)(21). Similarly, CCL22 expression in allografts promotes Treg accumulation and prevents graft rejection (20,22,23), and induction of CCL22 in the pancreas of nonobese diabetic mice promoted Treg accumulation, protecting against tissue destruction and autoimmune diabetes (24).…”