Xu-Monette, Ziju YXiao, MinAu, QingyanPadmanabhan, RaghavXu, BingHoe, NicholasRodriguez Perales, SandraTorres-Ruiz, RaulManyam, Ganiraju CVisco, CarloMiao, YiTan, XiaohongZhang, HongweiTzankov, AlexandarWang, JingDybkær, KarenTam, WayneYou, HuaBhagat, GovindHsi, Eric DPonzoni, MaurilioFerreri, Andrés J MMøller, Michael BPiris, Miguel Avan Krieken, J HanWinter, Jane NWestin, Jason RPham, Lan VMedeiros, L JeffreyRassidakis, George ZLi, YongFreeman, Gordon JYoung, Ken H2025-01-272025-01-272019-04Cancer Immunol Res . 2019 Apr;7(4):644-657.https://hdl.handle.net/20.500.12105/26147This work is supported by the Sister Institution Network Fund at The University of Texas MD Anderson Cancer Center.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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/B-CELL LYMPHOMADEATH-LIGAND 1CD8 T-CELLSPD-1 BLOCKADEREGULATORY TCTLA-4SURVIVALHODKINGMEMBERPROLIFERATIONAttribution-NonCommercial-NoDerivatives 4.0 International3074536674644-657Cancer Immunol Resopen access