Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1-Specific VHHs

Cancer Immunol Res. 2018 Apr;6(4):389-401. doi: 10.1158/2326-6066.CIR-17-0495. Epub 2018 Feb 19.


Cytokine-based therapies for cancer have not achieved widespread clinical success because of inherent toxicities. Treatment for pancreatic cancer is limited by the dense stroma that surrounds tumors and by an immunosuppressive tumor microenvironment. To overcome these barriers, we developed constructs of single-domain antibodies (VHHs) against PD-L1 fused with IL-2 and IFNγ. Targeting cytokine delivery in this manner reduced pancreatic tumor burden by 50%, whereas cytokines fused to an irrelevant VHH, or blockade of PD-L1 alone, showed little effect. Targeted delivery of IL-2 increased the number of intratumoral CD8+ T cells, whereas IFNγ reduced the number of CD11b+ cells and skewed intratumoral macrophages toward the display of M1-like characteristics. Imaging of fluorescent VHH-IFNγ constructs, as well as transcriptional profiling, demonstrated targeting of IFNγ to the tumor microenvironment. Many tumors and tumor-infiltrating myeloid cells express PD-L1, rendering them potentially susceptible to this form of targeted immunotherapy. Cancer Immunol Res; 6(4); 389-401. ©2018 AACR.

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 / genetics
  • B7-H1 Antigen / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytokines / antagonists & inhibitors
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Humans
  • Melanoma, Experimental
  • Mice
  • Molecular Targeted Therapy
  • Pancreatic Neoplasms / diagnosis
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / therapy
  • Single-Domain Antibodies / pharmacology*
  • Single-Domain Antibodies / therapeutic use
  • Tumor Microenvironment* / drug effects
  • Tumor Microenvironment* / immunology


  • B7-H1 Antigen
  • CD274 protein, human
  • Cytokines
  • Single-Domain Antibodies