Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer

ACS Nano. 2017 Sep 26;11(9):8690-8706. doi: 10.1021/acsnano.7b01786. Epub 2017 Aug 28.


Pancreatic tumors are known to be resistant to immunotherapy due to the extensive immune suppressive tumor microenvironment (TME). We hypothesized that CXCL12 and PD-L1 are two key molecules controlling the immunosuppressive TME. Fusion proteins, called traps, designed to bind with these two molecules with high affinity (Kd = 4.1 and 0.22 nM, respectively) were manufactured and tested for specific binding with the targets. Plasmid DNA encoding for each trap was formulated in nanoparticles and intravenously injected to mice bearing orthotopic pancreatic cancer. Expression of traps was mainly seen in the tumor, and secondarily, accumulations were primarily in the liver. Combination trap therapy shrunk the tumor and significantly prolonged the host survival. Either trap alone only brought in a partial therapeutic effect. We also found that CXCL12 trap allowed T-cell penetration into the tumor, and PD-L1 trap allowed the infiltrated T-cells to kill the tumor cells. Combo trap therapy also significantly reduced metastasis of the tumor cells to other organs. We conclude that the trap therapy significantly modified the immunosuppressive TME to allow the host immune system to kill the tumor cells. This can be an effective therapy in clinical settings.

Keywords: CXCL12; PD-L1; allograft model; pancreatic ductal adenocarcinoma; trap protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology*
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / therapy*
  • Chemokine CXCL12 / antagonists & inhibitors
  • Chemokine CXCL12 / immunology*
  • DNA / therapeutic use*
  • Genetic Therapy / methods
  • Immunotherapy / methods*
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Tumor Escape
  • Tumor Microenvironment


  • B7-H1 Antigen
  • Chemokine CXCL12
  • DNA