CCR4 Blockade Diminishes Intratumoral Macrophage Recruitment and Augments Survival of Syngeneic Pancreatic Cancer-Bearing Mice
Aydar Khabipov,
Dung Nguyen Trung,
Julia van der Linde,
Lea Miebach,
Maik Lenz,
Felix Erne,
Wolfram von Bernstorff,
Tobias Schulze,
Stephan Kersting,
Sander Bekeschus,
Lars Ivo Partecke
Affiliations
Aydar Khabipov
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Dung Nguyen Trung
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Julia van der Linde
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Lea Miebach
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Maik Lenz
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Felix Erne
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Wolfram von Bernstorff
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Tobias Schulze
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Stephan Kersting
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Sander Bekeschus
ZIK <i>plasmatis</i>, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str. 2, 17489 Greifswald, Germany
Lars Ivo Partecke
Department of General, Thoracic, Visceral, and Vascular Surgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany
Pancreatic cancer is known for its tumor microenvironment (TME), which is rich in stromal and immune cells supporting cancer growth and therapy resistance. In particular, tumor-associated macrophages (TAMs) are known for their angiogenesis- and metastasis-promoting properties, which lead to the failure of conventional therapies for pancreatic cancer. Hence, treatment options targeting TAMs are needed. The C-C chemokine receptor type 4 (CCR4) is critical for immune cell recruitment into the TME, and in this paper we explore the effects of its genetic or immunotherapeutic blockade in pancreatic-cancer-bearing mice. Murine PDA6606 pancreatic cancer cells and murine peritoneal macrophages were used for in vitro migration assays. In vivo, a syngeneic, orthotropic pancreatic cancer model was established. Tumor growth and survival were monitored under prophylactic and therapeutic application of a CCR4 antagonist (AF-399/420/18025) in wildtype (CCR4wt) and CCR4-knockout (CCR4−/−) mice. Immune infiltration was monitored in tumor tissue sections and via flow cytometry of lysed tumors. PDA6606 cells induced less migration in CCR4−/− than in CCR4wt macrophages in vitro. Pancreatic TAM infiltration was higher, and survival was reduced in CCR4wt mice compared to CCR4−/− mice. Antagonizing CCR4 in wildtype mice revealed similar results as in CCR4−/− mice without antagonization. Prophylactic CCR4 antagonist application in wildtype mice was more efficient than therapeutic antagonization. CCR4 seems to be critically involved in TAM generation and tumor progression in pancreatic cancer. CCR4 blockade may help prolong the relapse-free period after curative surgery in pancreatic cancer and improve prognosis.
