Zijun Xu-Monette

Overview:

My research efforts have been focused on identifying prognostic and therapeutic biomarkers in B-cell lymphoma. My research interests also include investigation of molecular and immune mechanisms underlying the poor clinical outcomes of lymphoma, the pathogenesis and evolution of drug resistant clones, and development of novel therapies for aggressive B-cell lymphoma.

Positions:

Assistant Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2009

Michigan Technological University

Grants:

Publications:

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

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.
Authors
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
MLA Citation
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. Epmc, doi:10.1182/blood-2018-03-841015.
URI
https://scholars.duke.edu/individual/pub1404994
PMID
30209121
Source
epmc
Published In
Blood
Volume
132
Published Date
Start Page
1805
End Page
1817
DOI
10.1182/blood-2018-03-841015

PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?

PD-1-PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1-PD-L1 axis is affected by the complex immunologic regulation network, and some CD8+ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD-L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer.
Authors
Xu-Monette, ZY; Zhang, M; Li, J; Young, KH
MLA Citation
Xu-Monette, Zijun Y., et al. “PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response?.” Front Immunol, vol. 8, 2017. Pubmed, doi:10.3389/fimmu.2017.01597.
URI
https://scholars.duke.edu/individual/pub1405001
PMID
29255458
Source
pubmed
Published In
Frontiers in Immunology
Volume
8
Published Date
Start Page
1597
DOI
10.3389/fimmu.2017.01597

Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma.

Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors.
Authors
Ye, Q; Xu-Monette, ZY; Tzankov, A; Deng, L; Wang, X; Manyam, GC; Visco, C; Montes-Moreno, S; Zhang, L; Dybkær, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; van Krieken, JH; Huh, J; Ponzoni, M; Ferreri, AJM; Parsons, BM; Møller, MB; Piris, MA; Winter, JN; Medeiros, LJ; Hu, S; Young, KH
MLA Citation
Ye, Qing, et al. “Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma..” Oncotarget, vol. 7, no. 3, Jan. 2016, pp. 2401–16. Pubmed, doi:10.18632/oncotarget.6262.
URI
https://scholars.duke.edu/individual/pub1405015
PMID
26573234
Source
pubmed
Published In
Oncotarget
Volume
7
Published Date
Start Page
2401
End Page
2416
DOI
10.18632/oncotarget.6262

Prognostic Significance of Survivin Expression in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Report from the International DLBCL Rituximab-CHOP Consortium Program

Authors
Liu, Z; Xu-Monette, ZY; Cao, X; Visco, C; Tzankov, A; Montes-Moreno, S; Dybkær, K; Chiu, A; Orazi, A; Zu, Y; Bhagat, G; Richards, KL; Hsi, ED; Choi, WWL; Han van Krieken, J; Huh, J; Ai, W; Ponzoni, M; Ferreri, AJM; Farnen, JP; Møller, MB; Winter, JN; Piris, MA; Medeiros, LJ; Young, KH
MLA Citation
Liu, Zhiyu, et al. “Prognostic Significance of Survivin Expression in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Report from the International DLBCL Rituximab-CHOP Consortium Program.” Clinical Lymphoma Myeloma and Leukemia, vol. 15, Elsevier BV, 2015, pp. S216–S216. Crossref, doi:10.1016/j.clml.2015.04.087.
URI
https://scholars.duke.edu/individual/pub1405126
Source
crossref
Published In
Clinical Lymphoma, Myeloma & Leukemia
Volume
15
Published Date
Start Page
S216
End Page
S216
DOI
10.1016/j.clml.2015.04.087

Erratum: Prevalence and clinical implications of epstein-barr virus infection inDeNovo diffuse large B-Cell lymphoma in Western Countries (Clin Cancer Res (2014) 20 (2338-2349))

Authors
Ok, CY; Li, L; Xu-Monette, ZY; Visco, C; Tzankov, A; Manyam, GC
MLA Citation
Ok, C. Y., et al. “Erratum: Prevalence and clinical implications of epstein-barr virus infection inDeNovo diffuse large B-Cell lymphoma in Western Countries (Clin Cancer Res (2014) 20 (2338-2349)).” Clinical Cancer Research, vol. 20, no. 18, Sept. 2014. Scopus, doi:10.1158/1078-0432.CCR-14-1858.
URI
https://scholars.duke.edu/individual/pub1405036
Source
scopus
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
20
Published Date
Start Page
4974
DOI
10.1158/1078-0432.CCR-14-1858