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

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.

Author information

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China.
Navigate BioPharma Services, Inc., a Novartis subsidiary, Carlsbad, CA, USA.
Department of Hematology, The First Affiliated Hospital of Xiamen University, Fujian, China.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Histopathology, University Hospital of Basel, Basel, Switzerland.
San Bortolo Hospital, Vicenza, Italy.
Aalborg University Hospital, Aalborg, Denmark.
New York-Presbyterian/Columbia University Medical Center, New York, NY, USA.
Weill Cornell Medicine, Cornell University, New York, NY, USA.
Department of Pathology, Cleveland Clinic, Cleveland, OH, USA.
Radboud University Medical Centre, Nijmegen, Netherlands.
Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
San Raffaele H. Scientific Institute, Milan, Italy.
Odense University Hospital, Odense, Denmark.
Marqués de Valdecilla University Hospital, Santander, Spain.
Department of Oncology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, China.
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Karolinska Institutet, Karolinska University Hospital, Solna, Sweden.
Navigate BioPharma Services, Inc., a Novartis subsidiary, Carlsbad, CA, USA.
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.


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.


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