The effects of CCR5 inhibition on regulatory T-cell recruitment to colorectal cancer

Abstract

Background:Regulatory T cells (Treg) are enriched in human colorectal cancer (CRC) where they suppress anti-tumour immunity. The chemokine receptor CCR5 has been implicated in the recruitment of Treg from blood into CRC and tumour growth is delayed in CCR5−/− mice, associated with reduced tumour Treg infiltration.Methods:Tissue and blood samples were obtained from patients undergoing resection of CRC. Tumour-infiltrating lymphocytes were phenotyped for chemokine receptors using flow cytometry. The presence of tissue chemokines was assessed. Standard chemotaxis and suppression assays were performed and the effects of CCR5 blockade were tested in murine tumour models.Results:Functional CCR5 was highly expressed by human CRC infiltrating Treg and CCR5high Treg were more suppressive than their CCR5low Treg counterparts. Human CRC-Treg were more proliferative and activated than other T cells suggesting that local proliferation could provide an alternative explanation for the observed tumour Treg enrichment. Pharmacological inhibition of CCR5 failed to reduce tumour Treg infiltration in murine tumour models although it did result in delayed tumour growth.Conclusions:CCR5 inhibition does not mediate anti-tumour effects as a consequence of inhibiting Treg recruitment. Other mechanisms must be found to explain this effect. This has important implications for anti-CCR5 therapy in CRC.

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

“…However, the relationship between CCL5 and T regs recruitment has not been explored. The chemokines CCL5 and CCL22 have been reported to be responsible for T reg recruitment [27,30,35,44]. In this study, we showed that CCL5 could attract T regs , and CD133 1 -CM recruited more T regs than did CD133 --CM, which could be blocked by antibodies against human CCL5, suggesting that the recruitment of T regs by CSCs rely upon CCL5.…”

“…T regs from ovarian cancer patients expressed higher levels of CCR5 than T regs from healthy controls Cells expressing CCL5 and its receptor CCR5 were attracted via chemokine-receptor interactions [30,35]. It has been demonstrated that CCR5 is involved in the recruitment of T regs in mice [35].…”

“…However, the immune system often fails to eliminate cancer cells. It has been demonstrated that tumour cells develop potent, overlapping mechanisms to foster immune privilege by including the infiltration of T regs into the tumour microenvironment [27][28][29][30]. T regs enriched in ovarian carcinoma lead to reduced survival [27] and this has also been observed in many other solid tumours, including melanomas, renal cancer, breast cancer, cervical cancer [31] and colorectal cancer [32].…”

“…T regs infiltrate into tumour sites via various mechanisms, such as trafficking, differentiation, expansion and conversion [33]. C-C motif chemokine ligand 22 (CCL22) [27,34], CCL5 [30,35] and CCL28 [28] are responsible for trafficking, while TGF-b and DCs are associated with the activation of T regs induction in the tumour microenvironment [33].…”

CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells

“…Some authors reported higher CCR5 expression in primary CRC with increased local growth [20,21], while others have found that high CCR5 expression is required for metastasis [22,23]. In addition to this, it is presumed that variations in expressional pattern of CCR5 can alter the immune response system in CRC, which in turn will favor the further progression of the disease [24][25][26][27][28].…”