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Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.

Publication ,  Journal Article
Xu-Monette, ZY; Xiao, M; Au, Q; Padmanabhan, R; Xu, B; Hoe, N; Rodríguez-Perales, S; Torres-Ruiz, R; Manyam, GC; Visco, C; Miao, Y; Tan, X ...
Published in: Cancer Immunol Res
April 2019

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 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-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.

Duke Scholars

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Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

April 2019

Volume

7

Issue

4

Start / End Page

644 / 657

Location

United States

Related Subject Headings

  • Vincristine
  • Tumor Microenvironment
  • T-Lymphocytes
  • Rituximab
  • Programmed Cell Death 1 Receptor
  • Prognosis
  • Prednisone
  • Phenotype
  • Middle Aged
  • Lymphoma, Large B-Cell, Diffuse
 

Citation

APA
Chicago
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MLA
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Xu-Monette, Z. Y., Xiao, M., Au, Q., Padmanabhan, R., Xu, B., Hoe, N., … 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 Immunol Res, 7(4), 644–657. https://doi.org/10.1158/2326-6066.CIR-18-0439
Xu-Monette, Ziju Y., Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodríguez-Perales, et al. “Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.Cancer Immunol Res 7, no. 4 (April 2019): 644–57. https://doi.org/10.1158/2326-6066.CIR-18-0439.
Xu-Monette ZY, Xiao M, Au Q, Padmanabhan R, Xu B, Hoe N, et al. Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL. Cancer Immunol Res. 2019 Apr;7(4):644–57.
Xu-Monette, Ziju Y., et al. “Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.Cancer Immunol Res, vol. 7, no. 4, Apr. 2019, pp. 644–57. Pubmed, doi:10.1158/2326-6066.CIR-18-0439.
Xu-Monette ZY, Xiao M, Au Q, Padmanabhan R, Xu B, Hoe N, Rodríguez-Perales S, Torres-Ruiz R, Manyam GC, Visco C, Miao Y, Tan X, Zhang H, Tzankov A, Wang J, Dybkær K, Tam W, You H, Bhagat G, Hsi ED, Ponzoni M, Ferreri AJM, Møller MB, Piris MA, van Krieken JH, Winter JN, Westin JR, Pham LV, Medeiros LJ, Rassidakis GZ, Li Y, Freeman GJ, Young KH. Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL. Cancer Immunol Res. 2019 Apr;7(4):644–657.

Published In

Cancer Immunol Res

DOI

EISSN

2326-6074

Publication Date

April 2019

Volume

7

Issue

4

Start / End Page

644 / 657

Location

United States

Related Subject Headings

  • Vincristine
  • Tumor Microenvironment
  • T-Lymphocytes
  • Rituximab
  • Programmed Cell Death 1 Receptor
  • Prognosis
  • Prednisone
  • Phenotype
  • Middle Aged
  • Lymphoma, Large B-Cell, Diffuse