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

Ziju Y. Xu-Monette, Min Xiao, Qingyan Au*, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodríguez-Perales, Raul Torres-Ruiz, Ganiraju C. Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkær, Wayne Tam, Hua You, Govind Bhagat, Eric D. HsiMaurilio Ponzoni, Andres 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, Ken H. Young

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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 de novo DLBCL using a MultiOmyx immu-nofluorescence 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-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 results 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.

Original languageEnglish (US)
Pages (from-to)644-657
Number of pages14
JournalCancer Immunology Research
Volume7
Issue number4
DOIs
StatePublished - Apr 2019

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ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Xu-Monette, Z. Y., Xiao, M., Au, Q., Padmanabhan, R., Xu, B., Hoe, N., Rodríguez-Perales, S., Torres-Ruiz, R., Manyam, G. C., Visco, C., Miao, Y., Tan, X., Zhang, H., Tzankov, A., Wang, J., Dybkær, K., Tam, W., You, H., Bhagat, G., ... Young, K. H. (2019). Immune profiling and quantitative analysis decipher the clinical role of immune-checkpoint expression in the tumor immune microenvironment of DLBCL. Cancer Immunology Research, 7(4), 644-657. https://doi.org/10.1158/2326-6066.CIR-18-0439