CCR5-Dependent Homing of T Regulatory Cells to the Tumor Microenvironment Contributes to Skin Squamous Cell Carcinoma Development

Abstract

Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4CD25CCR5, CD4CD25CCR5 or CD8CCR5 conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4CD25CCR5 cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8 T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. .

ZipSeq : Barcoding for Real-time Mapping of Single Cell Transcriptomes

“…We also noted the enhanced expression of chemokines/receptors in interior vs. margin CD8 T cells associated with increased trafficking and infiltration of T cells into the tumor such as Ccl4/5 and receptor Ccr5 (Fig. 4L) [40][41][42] .…”

Cytokine/chemokine profiles in squamous cell carcinoma correlate with precancerous and cancerous disease stage

“…For example, accumulation of CCR5 + myeloid-derived suppressor cells in a mouse model of melanoma is associated with local up-regulation of CCR5 ligands (CCL3/MIP-1α, CCL4/MIP-1β and CCL5/RANTES) 23 . Similarly, regulatory T cells have also been reported to home to a mouse model of cutaneous SCC via CCR5 signalling 24 . In both examples, the CCR5 chemokine signalling pathway is paramount to the immunosuppressive tumour microenvironment 23,24 .…”

The Ins and Outs of Chemokine-Mediated Immune Cell Trafficking in Skin Cancer

“…Cutaneous overexpression of CCL22 led to diversion of Tregs from pulmonary melanoma metastases to the skin, leading to inhibition of metastatic growth in the lungs (33). Other studies have shown CCR5-dependent recruitment of Tregs into melanoma and SCC (8, 95), while the ligands for this receptor were produced by MDSCs (8). Consistent with this, CCR5-deficient mice demonstrated slower rate of melanoma growth (8, 95).…”

“…Other studies have shown CCR5-dependent recruitment of Tregs into melanoma and SCC (8, 95), while the ligands for this receptor were produced by MDSCs (8). Consistent with this, CCR5-deficient mice demonstrated slower rate of melanoma growth (8, 95). In another study, B16 melanoma cells overexpressing CCL21 displayed increased growth potential and on injection induced a more suppressive tumor environment containing increased Tregs and TGFβ but decreased IFN-γ levels (9).…”