PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program

Mod Pathol. 2019 Jun;32(6):741-754. doi: 10.1038/s41379-018-0193-5. Epub 2019 Jan 21.


Programmed cell death protein 1/programmed cell death protein ligand1 (PD-1/PD-L1) interaction is an important immune checkpoint targeted by anti-PD-1/PD-L1 immunotherapies. However, the observed prognostic significance of PD-1/PD-L1 expression in diffuse large B-cell lymphoma treated with the standard of care has been inconsistent and even contradictory. To clarify the prognostic role of PD-1/PD-L1 expression and interaction in diffuse large B-cell lymphoma, in this study we used 3-marker fluorescent multiplex immunohistochemistry and Automated Quantitative Analysis Technology to assess the CD3+, PD-L1+, and PD-1+CD3+ expression in diagnostic samples and PD-1/PD-L1 interaction as indicated by presence of PD-1+CD3+ cells in the vicinity of PD-L1+ cells, analyzed their prognostic effects in 414 patients with de novo diffuse large B-cell lymphoma, and examined whether PD-1/PD-L1 interaction is required for the prognostic role of PD-1+/PD-L1+ expression. We found that low T-cell tissue cellularity, tissue PD-L1+ expression (irrespective of cell types), PD-1+CD3+ expression, and PD-1/PD-L1 interaction showed hierarchical adverse prognostic effects in the study cohort. PD-1/PD-L1 interaction showed higher sensitivity and specificity than PD-1+ and PD-L1+ expression in predicting inferior prognosis in patients with high CD3+ tissue cellularity ("hot"/inflammatory tumors). However, both PD-1+ and PD-L1+ expression showed adverse prognostic effects independent of PD-1/PD-L1 interaction, and PD-1/PD-L1 interaction showed favorable prognostic effect in PD-L1+ patients without high CD3+ tissue cellularity. Macrophage function and tumor-cell MYC expression may contribute to the PD-1-independent adverse prognostic effect of PD-L1+ expression. In summary, low T-cell tissue cellularity has unfavorable prognostic impact in diffuse large B-cell lymphoma, and tissue PD-L1+ expression and T-cell-derived PD-1+ expression have significant adverse impact only in patients with high T-cell infiltration. PD-1/PD-L1 interaction in tissue is essential but not always responsible for the inhibitory effect of PD-L1+/PD-1+ expression. These results suggest the benefit of PD-1/PD-L1 blockade therapies only in patients with sufficient T-cell infiltration, and the potential of immunofluorescent assays and Automated Quantitative Analysis in the clinical assessment of PD-1/PD-L1 expression and interaction.

MeSH terms

  • Aged
  • B7-H1 Antigen / biosynthesis
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / immunology
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Lymphocytes, Tumor-Infiltrating / pathology*
  • Lymphoma, Large B-Cell, Diffuse / pathology*
  • Male
  • Middle Aged
  • Prognosis
  • Programmed Cell Death 1 Receptor / biosynthesis
  • T-Lymphocytes / pathology*
  • Tumor Microenvironment / immunology*


  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor