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

ABSTRACT: 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.

SUBMITTER: Li L

PROVIDER: S-EPMC6634963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAntitumor immune response of programmed cell death ligand (PD-L1) has shown clinical value not only in Hodgkin lymphoma and EBV-associated lymphomas but also in EBV-negative diffuse large B cell lymphoma (DLBCL) of non-germinal center B cell-like (non-GCB) subtype. Signal transducer and activator of transcription 3 (STAT3) is known to induce PD-L1 in immune cells and its activated form, phosphorylated STAT3 (pSTAT3), is also frequently expressed in non-GCB DLBCL. Herein, we investigated associations between PD-L1 expression/gene alteration, pSTAT3 expression and clinicopathologic variables in EBV-negative DLBCL.MethodsIn 107 cases of DLBCLs with non-GCB subtype (67%; 72/107), GCB subtype (25%; 27/107) and unclassifiable cases (8%; 8/107), we performed PD-L1 and pSTAT3 immunohistochemistry and fluorescence in situ hybridization for PD-L1 gene translocation and copy number gain/amplification.ResultsPD-L1 was expressed in tumor cells (PD-L1t) in 21% (23/107; 30% cutoff), immune cells (PD-L1i) in 36% (38/107; 20% cutoff), and pSTAT3 in tumor nuclei in 41% (44/107; 40% cutoff). PD-L1 gene alteration was observed in 10% (10/102) including translocation in 6% (6/102) and copy number gain/amplification in 4% (4/102). Non-GCB subtype was associated with PD-L1t and pSTAT3 (p = 0.006 and p = 0.042), and tended to have PD-L1 gene alteration (p = 0.058). Tumoral PD-L1 expression without gene alteration (PD-L1t+ GA-) correlated with pSTAT3-positive tumor cell proportions (%) (p = 0.033). In survival analysis, pSTAT3 expression independently predicted shorter PFS in total cohort (p = 0.017) and R-CHOP-treated group (p = 0.007), and in pSTAT3-negative R-CHOP-treated subset, PD-L1 expression in immune cells (PD-L1i) correlated with shorter PFS (p = 0.042).ConclusionsGene alteration and protein expression of PD-L1 and pSTAT3 expression were closely related in DLBCL and constituted features of non-GCB subtype. In addition to known clinical significance of pSTAT3, immune cell expression of PD-L1 (PD-L1i) had also clinical value in pSTAT3-dependent manner. These findings may provide an insight into immunotherapeutic strategy and risk stratification in DLBCL patients.

Project description:This study aimed to investigate PD-L1 and PD-1 expression in circulating CD20+ cells in diffuse larger B-cell lymphoma (DLBCL) and to evaluate the predictive and diagnostic performance of PD-L1 versus PD-1 expression in circulating CD20+ cells in DLBCL. Percentages of CD20+, PD-L1+CD20+, and PD-1+CD20+ cells were measured by flow cytometry in 40 DLBCL blood samples and 19 healthy controls. The DLBCL patient group was subdivided into 20 newly diagnosed patients with no treatment yet and 20 patients that had finished six cycles of CHOP therapy. Percentages of PD-L1+CD20+ and PD-1+CD20+ cells were highly significantly increased in pre-therapy patients in comparison to healthy volunteers (p < 0.001). Meanwhile, a significant decrease in percentages of PD-L1+CD20+ and PD-1+CD20+ was observed in post-CHOP therapy patients in comparison to pre-therapy patients (p < 0.001). PD-L1+CD20+ cells were significantly decreased in post-therapy patients when compared to normal controls (p < 0.001), while not for PD-1+CD20+ cells. A strong significant positive correlation between percentages of PD-L1+CD20+ and PD-1+CD20+ was detected in DLBCL patients (p < 0.001). In the pre-therapy group, high PD-L1+CD20+ and PD-1+CD20+ percentages were correlated with serum LDH levels (p = 0.021, p < 0.001). High percentages of PD-1+CD20+ were found in DLBCL patients with splenomegaly (p = 0.027). The results revealed that patients with advanced tumor stages, poor ECOG performance, and non-GCB DLBCL type had increased percentages of PD-L1+CD20+ and PD-1+CD20+ cells. Moreover, PD-L1+CD20+ % and PD-1+CD20+ % were significantly increased in DLBCL patients with bone marrow involvement or B symptoms. The superiority of PD-L1+CD20+ over PD-1+CD20+ was more profound in DLBCL prediction [AUC: 1.0] and in discriminating newly diagnosed patients [AUC: 1.0]. The findings suggest that increased PD-L1/PD-1 expression in peripheral CD20 cells may serve as a companion diagnostic marker for DLBCL. Moreover, percentages of PD-L1+CD20+ cells have better diagnostic performance with higher sensitivity and specificity than PD-1+CD20+ %.

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

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