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B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.

Publication ,  Journal Article
Li, L; Zhang, J; Chen, J; Xu-Monette, ZY; Miao, Y; Xiao, M; Young, KH; Wang, S; Medeiros, LJ; Wang, M; Ford, RJ; Pham, LV
Published in: Blood
October 25, 2018

Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1+ B-cell lymphoma cells. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in 2 primary DLBCL cohorts consisting of 428 and 350 cases and showed significant correlations among IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.

Duke Scholars

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

October 25, 2018

Volume

132

Issue

17

Start / End Page

1805 / 1817

Location

United States

Related Subject Headings

  • Signal Transduction
  • STAT3 Transcription Factor
  • Receptors, Antigen, B-Cell
  • NFATC Transcription Factors
  • Lymphoma, Large B-Cell, Diffuse
  • Interleukin-10
  • Immunology
  • Humans
  • Gene Expression Regulation, Leukemic
  • B7-H1 Antigen
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Li, L., Zhang, J., Chen, J., Xu-Monette, Z. Y., Miao, Y., Xiao, M., … Pham, L. V. (2018). B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma. Blood, 132(17), 1805–1817. https://doi.org/10.1182/blood-2018-03-841015
Li, Li, Jun Zhang, Juan Chen, Zijun Y. Xu-Monette, Yi Miao, Min Xiao, Ken H. Young, et al. “B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.Blood 132, no. 17 (October 25, 2018): 1805–17. https://doi.org/10.1182/blood-2018-03-841015.
Li L, Zhang J, Chen J, Xu-Monette ZY, Miao Y, Xiao M, et al. B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma. Blood. 2018 Oct 25;132(17):1805–17.
Li, Li, et al. “B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.Blood, vol. 132, no. 17, Oct. 2018, pp. 1805–17. Pubmed, doi:10.1182/blood-2018-03-841015.
Li L, Zhang J, Chen J, Xu-Monette ZY, Miao Y, Xiao M, Young KH, Wang S, Medeiros LJ, Wang M, Ford RJ, Pham LV. B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma. Blood. 2018 Oct 25;132(17):1805–1817.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

October 25, 2018

Volume

132

Issue

17

Start / End Page

1805 / 1817

Location

United States

Related Subject Headings

  • Signal Transduction
  • STAT3 Transcription Factor
  • Receptors, Antigen, B-Cell
  • NFATC Transcription Factors
  • Lymphoma, Large B-Cell, Diffuse
  • Interleukin-10
  • Immunology
  • Humans
  • Gene Expression Regulation, Leukemic
  • B7-H1 Antigen