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Cancer Immunology Research

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Research Article

Immune profiling and quantitative analysis decipher the clinical role of immune checkpoint expression in the tumor immune microenvironment of DLBCL

Ziju Xu-Monette, Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Ganiraju Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkaer, Wayne Tam, Hua You, Govind Bhagat, Eric D. Hsi, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B Møller, Miguel A Piris, J Han van Krieken, Jane N Winter, Jason R. Westin, Lan V Pham, L. Jeffrey Medeiros, George Z Rassidakis, Yong Li, Gordon J. Freeman and Ken H Young
Ziju Xu-Monette
Hematopathology, University of Texas MD Anderson Cancer Center
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Min Xiao
Hematopathology, The University of Texas MD Anderson Cancer Center
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Qingyan Au
NeoGenomics
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Raghav Padmanabhan
NeoGenomics
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Bing Xu
Department of Heamatology, The First Affiliated Hospital of Xiamen University
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Nicholas Hoe
NeoGenomics
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Sandra Rodriguez-Perales
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO)
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Raul Torres-Ruiz
Spanish National Cancer Research Centre
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Ganiraju Manyam
Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center
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Carlo Visco
Hematology, San Bortolo Hospital
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Yi Miao
Hematopathology, The University of Texas MD Anderson Cancer Center
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Xiaohong Tan
Hematopathology, The University of Texas MD Anderson Cancer Center
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Hongwei Zhang
Hematopathology, The University of Texas MD Anderson Cancer Center
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Alexandar Tzankov
Pathology, University of Basel, Hospital
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  • ORCID record for Alexandar Tzankov
Jing Wang
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
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Karen Dybkaer
Department of Hematology, Aarhus University Hospital
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Wayne Tam
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine
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Hua You
Department of Lymphoma, Head and Neck Oncology,, Affiliated Hospital of the Academy of Military Medical Sciences
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Govind Bhagat
Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital
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Eric D. Hsi
Laboratory Medicine, Cleveland Clinic
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Maurilio Ponzoni
Pathology, San Raffaele Scientific Institute
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Andrés J.M. Ferreri
Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute
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Michael B Møller
Department of Pathology, Odense University Hospital
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Miguel A Piris
Hospital Universitario Marqués de Valdecilla
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J Han van Krieken
Radboud University Nijmegen Medical Centre
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Jane N Winter
Department of Medicine, Feinberg School of Medicine, Northwestern University
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Jason R. Westin
Lymphoma & Myeloma, MD Anderson
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Lan V Pham
Hematopathology, University of Texas MD Anderson Cancer Center
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L. Jeffrey Medeiros
Hematopathology, University of Texas MD Anderson Cancer Center
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George Z Rassidakis
Pathology and Cytology, Karolinska University Hospital & Karolinska Institute
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Yong Li
Cancer Biology, Cleveland Clinic Lerner Research Institute
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Gordon J. Freeman
Department of Medical Oncology, Dana-Farber Cancer Institute
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Ken H Young
Hematopathology, The University of Texas MD Anderson Cancer Center
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  • For correspondence: khyoung@mdanderson.org
DOI: 10.1158/2326-6066.CIR-18-0439
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Abstract

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for twelve types of cancer and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene expression profiling suggested the reversibility of T-cell exhaustion in PD-1+/PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab-CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

  • Received June 29, 2018.
  • Revision received September 23, 2018.
  • Accepted February 5, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst February 11, 2019
doi: 10.1158/2326-6066.CIR-18-0439

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Immune profiling and quantitative analysis decipher the clinical role of immune checkpoint expression in the tumor immune microenvironment of DLBCL
Ziju Xu-Monette, Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Ganiraju Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkaer, Wayne Tam, Hua You, Govind Bhagat, Eric D. Hsi, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B Møller, Miguel A Piris, J Han van Krieken, Jane N Winter, Jason R. Westin, Lan V Pham, L. Jeffrey Medeiros, George Z Rassidakis, Yong Li, Gordon J. Freeman and Ken H Young
Cancer Immunol Res February 11 2019 DOI: 10.1158/2326-6066.CIR-18-0439

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Immune profiling and quantitative analysis decipher the clinical role of immune checkpoint expression in the tumor immune microenvironment of DLBCL
Ziju Xu-Monette, Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Ganiraju Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkaer, Wayne Tam, Hua You, Govind Bhagat, Eric D. Hsi, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B Møller, Miguel A Piris, J Han van Krieken, Jane N Winter, Jason R. Westin, Lan V Pham, L. Jeffrey Medeiros, George Z Rassidakis, Yong Li, Gordon J. Freeman and Ken H Young
Cancer Immunol Res February 11 2019 DOI: 10.1158/2326-6066.CIR-18-0439
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