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Disruption of CCR5-Dependent Homing of Regulatory T Cells Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer¹

Marcus C. B. Tan^*, Peter S. Goedegebuure^*,, Brian A. Belt^*, Brian Flaherty^*, Narendra Sankpal^*, William E. Gillanders^*,, Timothy J. Eberlein^*,, Chyi-Song Hsieh and David C. Linehan^2,*,

^* Department of Surgery, Division of Rheumatology, Department of Medicine, and Siteman Cancer Center, Barnes-Jewish Hospital/Washington University Medical Center; St. Louis, MO 63110

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Frank Cancer Research Fund, awarded by the Barnes-Jewish Hospital Foundation. Tissue sectioning was performed through the Washington University Digestive Disease Research Core Center (Grant 5P30 DK052574).

² Address correspondence and reprint requests to Dr. David C. Linehan, Chief, Section of Hepato-Pancreato-Biliary and GI Surgery, Barnes-Jewish Hospital/Washington University School of Medicine, 660 South Euclid Avenue, Box 8109, St Louis, MO 63110. E-mail address: linehand{at}wustl.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; Teff, effector T cell; shRNA, small hairpin RNA; EpCAM, epithelial cell adhesion molecule; TAK-779, 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-aminium chloride; TDLN, tumor-draining lymph node; NLN, nondraining lymph node.

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