Potential genetic basis of B cell hyperactivation in murine lupus models

Lupus ◽  
2021 ◽  
pp. 096120332110182
Author(s):  
JY Ju ◽  
ZW Xu
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Early Response ◽  
Multiple Point ◽  
B Cell Activation ◽  
Murine Lupus ◽  
Activation Markers ◽  
Bcr Signaling ◽  
Abnormal Increase

Background Lupus B cells not only produce autoantibodies against nuclear antigens but also provide co-stimulation to T cells. However, there is still a lack of comprehensive understanding of the mechanism underlying lupus B cell hyperactivation. Methods This study focuses on the detection of B cell activation status, analysis of early BCR signaling response, DNA sequencing, and quantity determination of BCR signaling regulators in murine lupus models. Results Our result showed that there is a B cell hyperactivation with a significant elevation of B cell activation markers, and a BCR signaling hyperactivity with an abnormal increase of phosphorylated BCR signaling molecules and cytoplasmic calcium in the early response to BCR crosslinking in B6.Sle1/2/3 lupus mouse. Whole exome sequencing identified a multiple point mutation in the exon of many BCR signaling regulators in common murine lupus models, MRL/lpr, NZM2410, BXSB, NZB, and NZW strains. cNDA sequencing confirmed FcγR2b, Ly9, Pirb, Siglecg, and CD22 BCR signaling regulator variants in B6.Sle1/2/3 lupus mouse, but surface protein expression of these regulators on B cells showed an abnormal increase. Conclusion Our findings support that these BCR signaling regulator variants are potential causative genes of B cell hyperactivation in murine lupus models through their possible functional reduction.

scholarly journals Acute Csk inhibition hinders B cell activation by constraining the PI3 kinase pathway

2021 ◽  
Vol 118 (43) ◽  
pp. e2108957118
Author(s):  
Wen Lu ◽  
Katarzyna M. Skrzypczynska ◽  
Arthur Weiss
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Negative Regulator ◽  
B Cell Activation ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Bcr Signaling

T cell antigen receptor (TCR) and B cell antigen receptor (BCR) signaling are initiated and tightly regulated by Src-family kinases (SFKs). SFKs positively regulate TCR signaling in naïve T cells but have both positive and negative regulatory roles in BCR signaling in naïve B cells. The proper regulation of their activities depends on the opposing actions of receptor tyrosine phosphatases CD45 and CD148 and the cytoplasmic tyrosine kinase C-terminal Src kinase Csk. Csk is a major negative regulator of SFKs. Using a PP1-analog-sensitive Csk (CskAS) system, we have previously shown that inhibition of CskAS increases SFK activity, leading to augmentation of responses to weak TCR stimuli in T cells. However, the effects of Csk inhibition in B cells were not known. In this study, we surprisingly found that inhibition of CskAS led to marked inhibition of BCR-stimulated cytoplasmic free calcium increase and Erk activation despite increased SFK activation in B cells, contrasting the effects observed in T cells. Further investigation revealed that acute CskAS inhibition suppressed BCR-mediated phosphatidylinositol 3,4,5-trisphosphate (PIP3) production in B cells. Restoring PIP3 levels in B cells by CD19 cross-linking or SHIP1 deficiency eliminated the negative regulatory effect of CskAS inhibition. This reveals the critical role of Csk in maintaining an appropriate level of SFK activity and regulating PIP3 amounts as a means of compensating for SFK fluctuations to prevent inappropriate B cell activation. This regulatory mechanism controlling PIP3 amounts may also contribute to B cell anergy and self-tolerance.

scholarly journals An increase in circulating B cells and B cell activation markers in peripheral blood is associated with cigarette smoking in a male cohort in Bangladesh

2019 ◽  
Vol 384 ◽  
pp. 114783
Author(s):  
Scott W. Burchiel ◽  
Fredine T. Lauer ◽  
Pam Factor-Litvak ◽  
Xinhua Liu ◽  
Regina M. Santella ◽  
...  
Keyword(s):  
B Cells ◽  
Cigarette Smoking ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Activation ◽  
B Cell Activation ◽  
Activation Markers ◽  
Male Cohort

scholarly journals LPS stimulates IgM production in vivo without help from non-B cells

2016 ◽  
Vol 22 (5) ◽  
pp. 307-315 ◽  
Author(s):  
Mingfang Lu ◽  
Robert Munford
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Surface Expression ◽  
B Cell Activation ◽  
Direct Stimulation ◽  
Activation Markers ◽  
Necessary And Sufficient ◽  
Lps Signaling

Gram-negative bacterial LPS induce murine B-cell activation and innate (polyclonal) Ab production. Mouse B cells express the LPS signaling receptor (TLR4), yet how LPS activates B-cell responses in vivo is not known. Can LPS directly stimulate B cells to induce innate Ab production? Is activation of non-B cells also required? To address these questions, we transfused LPS-responsive ( Tlr4+/+) or non-responsive ( Tlr4−/−) B cells into LPS-responsive or non-responsive mice. Increased expression of the early activation markers CD69 and CD86 could be induced on transfused Tlr4−/− B cells by injecting LPS subcutaneously into Tlr4+/+ mice, demonstrating indirect activation of B cells by TLR4-responsive non-B cells in vivo, but the Tlr4−/− B cells did not increase serum IgM levels. In contrast, when Tlr4−/− recipients were transfused with Tlr4+/+ B cells, LPS induced large amounts of serum IgM and LPS could also enhance specific Ab production to a protein that was co-injected with it (adjuvant response). Thus, LPS-exposed non-B cells mediated increased surface expression of early B-cell activation markers, but this response did not predict innate Ab responses or LPS adjuvanticity in vivo. Direct stimulation of B cells by LPS via TLR4 was necessary and sufficient to induce B cells to produce Ab in vivo.

scholarly journals P063 B-cell receptor signalling in lymphoid tissues may be regulated by CEACAM1

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S166-S166
Author(s):  
T Nagaishi ◽  
N Tsugawa ◽  
D Yamada ◽  
T Watabe ◽  
M Onizawa ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Activation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphoid Tissues ◽  
B Cell Activation ◽  
Activation Markers

Abstract Background It has been recently shown that the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expressed in T cells may regulate immune responses in the gut. Moreover, it has also been reported that the treatments with either an agonistic monoclonal antibody (mAb) or natural ligands for this molecule can suppress colitis severity in murine models of inflammatory bowel diseases (IBD). On the other hand, in addition to T cells, B cells are also an important population in the gut-associated lymphoid tissues (GALT) that orchestrate mucosal homeostasis. However, the role of CEACAM1 in B cells has not been elucidated. Methods We analysed primary B-cell subsets in the lymphoid tissues of wild-type C57BL6 mice as well as a murine B-cell line, A20, to determine the expressions and functions of CEACAM1. Results FACS analysis of the lymphocyte subsets isolated from secondary lymphoid tissues such as spleen, mesenteric lymph nodes and Peyer’s patches of C57BL6 revealed higher expression level of CEACAM1 on B-cell surface than that of T cells. Bone marrow analysis showed that such CEACAM1 expression was increased during maturation and differentiation process of B cells. When isolated splenic B cells were stimulated with LPS, anti-CD40 or anti-μ chain Abs in the presence of agonistic anti-CEACAM1 mAb, the usual increased cytokine productions (such as IL-4 and IL-5 by activation via B cell receptor (BCR) signalling) were specifically suppressed by CEACAM1 signalling rather than B-cell activations via either TLR4 or CD40 signalling. Immunofluorescent studies using confocal microscopy revealed co-localisation of CEACAM1 and BCR when B cells were activated with anti-μ chain Ab. Given these results, A20 cells were transfected with CEACAM1 cDNA. Biochemical analysis showed that an inducible overexpression of CEACAM1 suppressed the BCR signalling in these cells when compared with that of vector alone-transfected control. Moreover, the overexpression of CEACAM1 in these cells resulted in reduced expressions of activation markers such as CD69, CD80, CD86, MHC-I and -II on the cell surface. These observations were associated with decreased Ca2+ influx and suppressed cytokine production by the overexpression of CEACAM1 after BCR signal activation. Conclusion These results suggest that CEACAM1 can regulate B-cell activation and differentiation specifically via BCR signalling in the lymphoid tissues. Therefore, this molecule can be a therapeutic target in IBD by regulating of both T-cell and B-cell activation in GALT.

scholarly journals APEX2 proximity biotinylation reveals protein dynamics triggered by B cell receptor activation

2020 ◽  
Author(s):  
Luqman O Awoniyi ◽  
Vid Šuštar ◽  
Sara Hernández-Pérez ◽  
Marika Vainio ◽  
Alexey V Sarapulov ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lipid Raft ◽  
Cell Activation ◽  
Kinetic Resolution ◽  
Cell Receptor ◽  
Receptor Activation ◽  
B Cell Receptor ◽  
B Cell Activation ◽  
Bcr Signaling

ABSTRACTB lymphocytes form a central part of the adaptive immune system, helping to clear infections by mounting antibody responses and immunological memory. B cell activation is critically controlled by a specific antigen receptor, the B cell receptor (BCR), which triggers a complex, multibranched signaling cascade initiating various cellular changes. While parts of these pathways are reasonably well characterized, we still lack a comprehensive protein-level view of the very dynamic and robust cellular response triggered by antigen engagement. Ability to track, with sufficient kinetic resolution, the protein machineries responding to BCR signaling is imperative to provide new understanding into this complex cell activation event. We address this challenge by using APEX2 proximity labeling technique, that allows capture a major fraction of proteins in a given location with 20nm range and 1min time window, and target the APEX2 enzyme to the plasma membrane lipid raft domain, where BCR efficiently translocates upon activation. Our data provides unprecedented insights into the protein composition of lipid raft environment in B cells, and the changes triggered there upon BCR cross-linking and translocation. In total, we identified 1677 proteins locating at the vicinity of lipid raft domains in cultured mouse B cells. The data includes a majority of proteins known to be involved in proximal BCR signaling. Interestingly, our differential enrichment analysis identified various proteins that underwent dynamic changes in their localization but that had no previously known linkage to early B cell activation. As expected, we also identified, for example, a wealth of proteins linked to clathrin-mediated endocytosis that were recruited to the lipid rafts upon cell activation. We believe that his data serves as a valuable record of proteins involved in BCR activation response and aid various future studies in the field.

CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1560-1569 ◽  
Author(s):  
Julia Sáez de Guinoa ◽  
Laura Barrio ◽  
Mario Mellado ◽  
Yolanda R. Carrasco
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Synapse Formation ◽  
Behavior Pattern ◽  
Lymphocyte Function ◽  
B Cell Activation ◽  
Cell Dynamics ◽  
Membrane Ruffling ◽  
Bcr Signaling

Abstract Continuous migration of B cells at the follicle contrasts with their stable arrest after encounter with antigen. Two main ligand/receptor pairs are involved in these cell behaviors: the chemokine CXCL13/chemokine receptor CXCR5 and antigen/BCR. Little is known regarding the interplay between CXCR5 and BCR signaling in the modulation of B-cell dynamics and its effect on B-cell activation. We used a 2-dimensional model to study B-cell migration and antigen recognition in real time, and found that BCR signaling strength alters CXCL13-mediated migration, leading to a heterogeneous B-cell behavior pattern. In addition, we demonstrate that CXCL13/CXCR5 signaling does not impair BCR-triggered immune synapse formation and that CXCR5 is excluded from the central antigen cluster. CXCL13/CXCR5 signaling enhances BCR-mediated B-cell activation in at least 2 ways: (1) it assists antigen gathering at the synapse by promoting membrane ruffling and lymphocyte function–associated antigen 1 (LFA-1)–supported adhesion, and (2) it allows BCR signaling integration in motile B cells through establishment of LFA-1–supported migratory junctions. Both processes require functional actin cytoskeleton and non-muscle myosin II motor protein. Therefore, the CXCL13/CXCR5 signaling effect on shaping B-cell dynamics is an effective mechanism that enhances antigen encounter and BCR-triggered B-cell activation.

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

scholarly journals AB0024 IN VITRO CHARACTERIZATION OF CENERIMOD, A POTENT AND SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR 1 (S1P1) MODULATOR IN PREVENTING MIGRATION OF NON-ACTIVATED AND ACTIVATED PRIMARY HUMAN B CELLS IN THE PRESENCE OR ABSENCE OF GLUCOCORTICOIDS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1046.1-1046
Author(s):  
L. Schlicher ◽  
P. Kulig ◽  
M. Murphy ◽  
M. Keller
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
B Cell Activation ◽  
Human B Cells ◽  
Circulating Lymphocytes

Background:Cenerimod is a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P1) modulator that is currently being evaluated in a Phase 2b study in patients with systemic lupus erythematosus (SLE) (NCT03742037). S1P1 receptor modulators sequester circulating lymphocytes within lymph nodes, thereby reducing pathogenic autoimmune cells (including B lymphocytes) in the blood stream and in inflamed tissues. Extensive clinical experience has become available for the nonselective S1P receptor modulator fingolimod in relapsing forms of multiple sclerosis, supporting this therapeutic concept for the treatment of autoimmune disorders.Objectives:Although the effect of S1P-receptor modulators in reducing peripheral B cells is well documented1,2, the role of the S1P1 receptor on this cell type is only incompletely understood. In this study, the mode of action of cenerimod on primary human B cells was investigated in a series of in vitro experiments, including S1P1 receptor cell surface expression and chemotaxis towards S1P. Moreover, S1P1 expression following B cell activation in vitro was studied. As glucocorticoids (GC) are frequently used in the treatment of patients with autoimmune disorders including SLE, the potential influence of GC on the mode of action of cenerimod was evaluated.Methods:Primary human B lymphocytes from healthy donors were isolated from whole blood. In one set of experiments, cells were treated with different concentrations of cenerimod to measure S1P1 receptor internalization by flow cytometry. In a second set of experiments, isolated B cells were activated using different stimuli or left untreated. Cells were then analysed for S1P1 and CD69 cell surface expression and tested in a novel real-time S1P-mediated migration assay. In addition, the effect of physiological concentrations of GCs (prednisolone and prednisone) on cenerimod activity in preventing S1P mediated migration was tested.Results:In vitro, cenerimod led to a dose-dependent internalization of the S1P1 receptor on primary human B lymphocytes. Cenerimod also blocked migration of nonactivated and activated B lymphocytes towards S1P in a concentration-dependent manner, which is in line with the retention of lymphocytes in the lymph node and the reduction of circulating lymphocytes observed in the clinical setting. Upon B cell activation, which was monitored by CD69 upregulation, a simultaneous downregulation of S1P1 expression was detected, leading to less efficient S1P-directed cell migration. Importantly, physiological concentrations of GC did not affect the inhibitory activity of cenerimod on B cell migration.Conclusion:These results show that cenerimod, by modulating S1P1, blocks B lymphocyte migration towards its natural chemoattractant S1P and demonstrate compatibility of cenerimod with GC. These results are consistent with results of comparable experiments done previously using primary human T lymphocytes.References:[1]Nakamura M et al., Mult Scler. 2014 Sep; 20(10):1371-80.[2]Strasser DS et al., RMD Open 2020;6:e001261.Disclosure of Interests:None declared

scholarly journals 702 Dual blockade of the PD-1 checkpoint pathway and the adenosinergic negative feedback signaling pathway with a PD-1/CD73 bispecific antibody for cancer immune therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A744-A744
Author(s):  
Tingting Zhong ◽  
Zhaoliang Huang ◽  
Xinghua Pang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Negative Feedback ◽  
Immune Suppression ◽  
Specific Antibody ◽  
Cell Activation ◽  
Immune Therapy ◽  
B Cell Activation

BackgroundCD73 (ecto-5’-nucleotidase) is an ecto-nucleotidase that dephosphorylate AMP to form adenosine. Activation of adenosine signaling pathway in immune cells leads to the suppression of effector functions, down-regulate macrophage phagocytosis, inhibit pro-inflammatory cytokine release, as well as yield aberrantly differentiated dendritic cells producing pro-tumorigenic molecules.1 In the tumor microenvironment, adenosinergic negative feedback signaling facilitated immune suppression is considered an important mechanism for immune evasion of cancer cells.2 3 Combination of CD73 and anti-PD-1 antibody has shown promising activity in suppressing tumor growth. Hence, we developed AK119, an anti- human CD73 monoclonal antibody, and AK123,a bi-specific antibody targeting both PD-1 and CD73 for immune therapy of cancer.MethodsAK119 is a humanized antibody against CD73 and AK123 is a tetrameric bi-specific antibody targeting PD-1 and CD73. Binding assays of AK119 and AK123 to antigens, and antigen expressing cells were performed by using ELISA, Fortebio, and FACS assays. In-vitro assays to investigate the activity of AK119 and AK123 to inhibit CD73 enzymatic activity in modified CellTiter-Glo assay, to induce endocytosis of CD73, and to activate B cells were performed. Assay to evaluate AK123 activity on T cell activation were additionally performed. Moreover, the activities of AK119 and AK123 to mediate ADCC, CDC in CD73 expressing cells were also evaluated.ResultsAK119 and AK123 could bind to its respective soluble or membrane antigens expressing on PBMCs, MDA-MB-231, and U87-MG cells with high affinity. Results from cell-based assays indicated that AK119 and AK123 effectively inhibited nucleotidase enzyme activity of CD73, mediated endocytosis of CD73, and induced B cell activation by upregulating CD69 and CD83 expression on B cells, and showed more robust CD73 blocking and B cell activation activities compared to leading clinical candidate targeting CD73. AK123 could also block PD-1/PD-L1 interaction and enhance T cell activation.ConclusionsIn summary, AK119 and AK123 represent good preclinical biological properties, which support its further development as an anti-cancer immunotherapy or treating other diseases.ReferencesDeaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007; 204:1257–65.Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood. 1997; 90:1600–10.Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y, Tikhomirov OY, Blackburn MR, Biaggioni I,Carbone DP, Feoktistov I, et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 2008; 112:1822–31.

scholarly journals Deep Phenotyping of CD11c+ B Cells in Systemic Autoimmunity and Controls

2021 ◽  
Vol 12 ◽  
Author(s):  
Hector Rincon-Arevalo ◽  
Annika Wiedemann ◽  
Ana-Luisa Stefanski ◽  
Marie Lettau ◽  
Franziska Szelinski ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
B Cell Activation ◽  
Membrane Expression ◽  
Ki 67 ◽  
Inflammatory Conditions ◽  
Systemic Autoimmunity ◽  
Enhanced Expression

Circulating CD11c+ B cells are a key phenomenon in certain types of autoimmunity but have also been described in the context of regular immune responses (i.e., infections, vaccination). Using mass cytometry to profile 46 different markers on individual immune cells, we systematically initially confirmed the presence of increased CD11c+ B cells in the blood of systemic lupus erythematosus (SLE) patients. Notably, significant differences in the expression of CD21, CD27, and CD38 became apparent between CD11c− and CD11c+ B cells. We observed direct correlation of the frequency of CD21−CD27− B cells and CD21−CD38− B cells with CD11c+ B cells, which were most pronounced in SLE compared to primary Sjögren's syndrome patients (pSS) and healthy donors (HD). Thus, CD11c+ B cells resided mainly within memory subsets and were enriched in CD27−IgD−, CD21−CD27−, and CD21−CD38− B cell phenotypes. CD11c+ B cells from all donor groups (SLE, pSS, and HD) showed enhanced CD69, Ki-67, CD45RO, CD45RA, and CD19 expression, whereas the membrane expression of CXCR5 and CD21 were diminished. Notably, SLE CD11c+ B cells showed enhanced expression of the checkpoint molecules CD86, PD1, PDL1, CD137, VISTA, and CTLA-4 compared to HD. The substantial increase of CD11c+ B cells with a CD21− phenotype co-expressing distinct activation and checkpoint markers, points to a quantitative increased alternate (extrafollicular) B cell activation route possibly related to abnormal immune regulation as seen under the striking inflammatory conditions of SLE which shows a characteristic PD-1/PD-L1 upregulation.

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