Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer

Clin Cancer Res. 2007 Apr 1;13(7):2151-7. doi: 10.1158/1078-0432.CCR-06-2746.

Abstract

Purpose: The programmed death-1 ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/PD-1 pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors.

Experimental design: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1 pathway in murine pancreatic cancer in vivo.

Results: PD-L1-positive patients had a significantly poorer prognosis than the PD-L1-negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8(+) T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8(+) T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti-PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity.

Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1 pathway against this fatal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Aged
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, CD / drug effects
  • Antigens, CD / metabolism*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • B7-H1 Antigen
  • Biomarkers, Tumor / analysis*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Female
  • Humans
  • Immunohistochemistry
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Peptides / metabolism
  • Prognosis
  • Programmed Cell Death 1 Ligand 2 Protein
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • PDCD1LG2 protein, human
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Deoxycytidine
  • gemcitabine