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oai:repisalud.isciii.es:20.500.12105/261472025-12-18T12:55:47Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Xu-Monette, Ziju Y author Xiao, Min author Au, Qingyan author Padmanabhan, Raghav author Xu, Bing author Hoe, Nicholas author Rodriguez Perales, Sandra author Torres-Ruiz, Raul author Manyam, Ganiraju C author Visco, Carlo author Miao, Yi author Tan, Xiaohong author Zhang, Hongwei author Tzankov, Alexandar author Wang, Jing author Dybkær, Karen author Tam, Wayne author You, Hua author Bhagat, Govind author Hsi, Eric D author Ponzoni, Maurilio author Ferreri, Andrés J M author Møller, Michael B author Piris, Miguel A author van Krieken, J Han author Winter, Jane N author Westin, Jason R author Pham, Lan V author Medeiros, L Jeffrey author Rassidakis, George Z author Li, Yong author Freeman, Gordon J author Young, Ken H author 2019-04 PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers 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 the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with 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 tumor 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-L1CD20 cells proximal (indicates interaction) to PD-1 CD8 T cells in patients with low PD-1 percentage of CD8 T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1/PD-L1 patients with unfavorable prognosis and implication of /, and 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. Cancer Immunol Res . 2019 Apr;7(4):644-657. Cancer Immunol Res 30745366 https://hdl.handle.net/20.500.12105/26147 B-CELL LYMPHOMA DEATH-LIGAND 1 CD8 T-CELLS PD-1 BLOCKADE REGULATORY T CTLA-4 SURVIVAL HODKING MEMBER PROLIFERATION Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.