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

• Published in: Molecular cancer therapeutics Vol. 16; no. 12; pp. 2871 - 2880
• Main Authors: de Oliveira, Carine Ervolino, Gasparoto, Thaís Helena, Pinheiro, Claudia Ramos, Amôr, Nádia Ghinelli, Nogueira, Maria Renata Sales, Kaneno, Ramon, Garlet, Gustavo Pompermaier, Lara, Vanessa Soares, Silva, João Santana, Cavassani, Karen Angélica, Campanelli, Ana Paula
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.12.2017
• Subjects: Adoptive transfer; Animals; Antitumor activity; Cancer; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; CCR5 protein; CD25 antigen; CD4 antigen; CD8 antigen; Chemokines; Cytotoxicity; Dendritic cells; Homing; Humans; Immune response; Immune system; Immunomodulation; Immunoregulation; Incidence; Infiltration; Inhibition; Lesions; Leukocyte migration; Lymphocytes; Lymphocytes T; Macrophages; Metastases; Mice; Papilloma; Receptors, CCR5 - immunology; Skin; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Squamous cell carcinoma; T-Lymphocytes, Regulatory - immunology; Tumor Microenvironment; Tumors
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-0341

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 CD4 CD25 CCR5 , CD4 CD25 CCR5 or CD8 CCR5 conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4 CD25 CCR5 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. .