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

Ling Li, Ruifang Sun, Yi Miao, Thai Tran, Lisa Adams, Nathan Roscoe, Bing Xu, Ganiraju C. Manyam, Xiaohong Tan, Hongwei Zhang, Min Xiao, Alexandar Tzankov, Carlo Visco, Karen Dybkaer, Govind Bhagat, Wayne Tam, Eric D. Hsi, J. Han van Krieken, Hua You, Jooryung Huh & 13 others Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B. Møller, Miguel A. Piris, Mingzhi Zhang, Jane Norma Winter, L. Jeffrey Medeiros, George Z. Rassidakis, Christine A. Vaupel, Yong Li, Naveen Dakappagari, Zijun Y. Xu-Monette, Ken H. Young*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)741-754
Number of pages14
JournalModern Pathology
Volume32
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

T-Cell Lymphoma
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
T-Lymphocytes
Programmed Cell Death 1 Receptor
Apoptosis Regulatory Proteins
Standard of Care
Immunotherapy
Neoplasms
Cohort Studies
Immunohistochemistry
Macrophages
Technology
Sensitivity and Specificity

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Li, Ling ; Sun, Ruifang ; Miao, Yi ; Tran, Thai ; Adams, Lisa ; Roscoe, Nathan ; Xu, Bing ; Manyam, Ganiraju C. ; Tan, Xiaohong ; Zhang, Hongwei ; Xiao, Min ; Tzankov, Alexandar ; Visco, Carlo ; Dybkaer, Karen ; Bhagat, Govind ; Tam, Wayne ; Hsi, Eric D. ; van Krieken, J. Han ; You, Hua ; Huh, Jooryung ; Ponzoni, Maurilio ; Ferreri, Andrés J.M. ; Møller, Michael B. ; Piris, Miguel A. ; Zhang, Mingzhi ; Winter, Jane Norma ; Medeiros, L. Jeffrey ; Rassidakis, George Z. ; Vaupel, Christine A. ; Li, Yong ; Dakappagari, Naveen ; Xu-Monette, Zijun Y. ; Young, Ken H. / 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. In: Modern Pathology. 2019 ; Vol. 32, No. 6. pp. 741-754.
@article{dd13144fccaf427998ea1c2c49b2e34a,
title = "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",
abstract = "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.",
author = "Ling Li and Ruifang Sun and Yi Miao and Thai Tran and Lisa Adams and Nathan Roscoe and Bing Xu and Manyam, {Ganiraju C.} and Xiaohong Tan and Hongwei Zhang and Min Xiao and Alexandar Tzankov and Carlo Visco and Karen Dybkaer and Govind Bhagat and Wayne Tam and Hsi, {Eric D.} and {van Krieken}, {J. Han} and Hua You and Jooryung Huh and Maurilio Ponzoni and Ferreri, {Andr{\'e}s J.M.} and M{\o}ller, {Michael B.} and Piris, {Miguel A.} and Mingzhi Zhang and Winter, {Jane Norma} and Medeiros, {L. Jeffrey} and Rassidakis, {George Z.} and Vaupel, {Christine A.} and Yong Li and Naveen Dakappagari and Xu-Monette, {Zijun Y.} and Young, {Ken H.}",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41379-018-0193-5",
language = "English (US)",
volume = "32",
pages = "741--754",
journal = "Modern Pathology",
issn = "0893-3952",
publisher = "Nature Publishing Group",
number = "6",

}

Li, L, Sun, R, Miao, Y, Tran, T, Adams, L, Roscoe, N, Xu, B, Manyam, GC, Tan, X, Zhang, H, Xiao, M, Tzankov, A, Visco, C, Dybkaer, K, Bhagat, G, Tam, W, Hsi, ED, van Krieken, JH, You, H, Huh, J, Ponzoni, M, Ferreri, AJM, Møller, MB, Piris, MA, Zhang, M, Winter, JN, Medeiros, LJ, Rassidakis, GZ, Vaupel, CA, Li, Y, Dakappagari, N, Xu-Monette, ZY & Young, KH 2019, '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', Modern Pathology, vol. 32, no. 6, pp. 741-754. https://doi.org/10.1038/s41379-018-0193-5

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. / Li, Ling; Sun, Ruifang; Miao, Yi; Tran, Thai; Adams, Lisa; Roscoe, Nathan; Xu, Bing; Manyam, Ganiraju C.; Tan, Xiaohong; Zhang, Hongwei; Xiao, Min; Tzankov, Alexandar; Visco, Carlo; Dybkaer, Karen; Bhagat, Govind; Tam, Wayne; Hsi, Eric D.; van Krieken, J. Han; You, Hua; Huh, Jooryung; Ponzoni, Maurilio; Ferreri, Andrés J.M.; Møller, Michael B.; Piris, Miguel A.; Zhang, Mingzhi; Winter, Jane Norma; Medeiros, L. Jeffrey; Rassidakis, George Z.; Vaupel, Christine A.; Li, Yong; Dakappagari, Naveen; Xu-Monette, Zijun Y.; Young, Ken H.

In: Modern Pathology, Vol. 32, No. 6, 01.06.2019, p. 741-754.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

T2 - a study from the International DLBCL Consortium Program

AU - Li, Ling

AU - Sun, Ruifang

AU - Miao, Yi

AU - Tran, Thai

AU - Adams, Lisa

AU - Roscoe, Nathan

AU - Xu, Bing

AU - Manyam, Ganiraju C.

AU - Tan, Xiaohong

AU - Zhang, Hongwei

AU - Xiao, Min

AU - Tzankov, Alexandar

AU - Visco, Carlo

AU - Dybkaer, Karen

AU - Bhagat, Govind

AU - Tam, Wayne

AU - Hsi, Eric D.

AU - van Krieken, J. Han

AU - You, Hua

AU - Huh, Jooryung

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J.M.

AU - Møller, Michael B.

AU - Piris, Miguel A.

AU - Zhang, Mingzhi

AU - Winter, Jane Norma

AU - Medeiros, L. Jeffrey

AU - Rassidakis, George Z.

AU - Vaupel, Christine A.

AU - Li, Yong

AU - Dakappagari, Naveen

AU - Xu-Monette, Zijun Y.

AU - Young, Ken H.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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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U2 - 10.1038/s41379-018-0193-5

DO - 10.1038/s41379-018-0193-5

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JF - Modern Pathology

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