Disruption of CCR5-Dependent Homing of Regulatory T Cells Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer

• Published in: The Journal of immunology (1950) 2009-02, Vol.182 (3), p.1746-1755
• Main Authors: Tan, Marcus C. B, Goedegebuure, Peter S, Belt, Brian A, Flaherty, Brian, Sankpal, Narendra, Gillanders, William E, Eberlein, Timothy J, Hsieh, Chyi-Song, Linehan, David C
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - prevention & control; Animals; CCR5 Receptor Antagonists; Cell Line, Tumor; Cell Migration Inhibition - genetics; Cells, Cultured; Chemotaxis, Leukocyte - genetics; Chemotaxis, Leukocyte - immunology; Coculture Techniques; Disease Models, Animal; Gene Knock-In Techniques; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - prevention & control; Receptors, CCR5 - biosynthesis; Receptors, CCR5 - genetics; Receptors, CCR5 - physiology; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.182.3.1746

Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg). We have previously described increased prevalence of these cells in pancreatic adenocarcinoma, but it remains unclear what mechanisms are involved in recruiting Tregs into the tumor microenvironment. Here, we postulated that chemokines might direct Treg homing to tumor. We show, in both human pancreatic adenocarcinoma and a murine pancreatic tumor model (Pan02), that tumor cells produce increased levels of ligands for the CCR5 chemokine receptor and, reciprocally, that CD4(+) Foxp3(+) Tregs, compared with CD4(+) Foxp3(-) effector T cells, preferentially express CCR5. When CCR5/CCL5 signaling is disrupted, either by reducing CCL5 production by tumor cells or by systemic administration of a CCR5 inhibitor (N,N-dimethyl-N-{{4-{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl}amino}}benzyl]-N,N-dimethyl-N- {{{4-{{{[2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptan-8-yl]carbonyl}amino}}benzyl}}}tetrahydro-2H-pyran-4-aminiumchloride; TAK-779), Treg migration to tumors is reduced and tumors are smaller than in control mice. Thus, this study demonstrates the importance of Tregs in immune evasion by tumors, how blockade of Treg migration might inhibit tumor growth, and, specifically in pancreatic adenocarcinoma, the role of CCR5 in the homing of tumor-associated Tregs. Selective targeting of CCR5/CCL5 signaling may represent a novel immunomodulatory strategy for the treatment of cancer.