scholarly journals 288 The COX-2 pathway as a mediator of resistance to anti-PD-1 therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A312-A312
Author(s):  
Shuming Chen ◽  
Tracee McMiller ◽  
Preethi Sankaran ◽  
Kyle Kampta ◽  
Suzanne Topalian
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Epstein Barr Virus ◽  
List Type ◽  
Tlr Agonists ◽  
Barr Virus ◽  
Immunosuppressive Tumor Microenvironment ◽  
Cox 2 ◽  
Context Dependent ◽  
Epstein Barr

BackgroundWe previously found upregulation of the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway in the tumor microenvironment (TME) of cancers that respond poorly to anti-PD-1 therapy.1–2 The potential functional role of this pathway in anti-PD-1 resistance is unknown. We therefore studied modulation of COX-2 expression in cultured human tumor and immune cells, PGE2-mediated effects on myeloid cells and their reversal with prostaglandin (EP) receptor inhibitors.MethodsNineteen tumor lines representing 6 histologies were treated with cytokines reported to induce COX-2 (IL-1B, IL-17A, TNF-a). Peripheral blood monocytes (Monos) were treated with toll-like receptor (TLR) agonists or TME-resident cytokines associated with high PD-L1 expression (IL-1A, IL-10, IL-27, IL-32g, IFN-g).3–4 COX-2 protein was detected by Western blotting and flow cytometry. In some experiments, Monos were pre-incubated with EP2i (PF-04418948) and/or EP4i (ONO-AE3-208), then treated with PGE2 ± TLR4 (LPS) or TLR7 (imiquimod) agonists. IL-6, IL-10, TNF-a, and VEGF secretion were detected by ELISA. Monocytic DCs generated with GM-CSF+IL-4 were matured with CD40L, ± PGE2, then phenotyped.ResultsAmong 19 tumor cell lines, 6 expressed COX-2 constitutively, and 13 were induced to express COX-2 by 1-day exposure to IL-1B, IL-17A, or TNF-a. In Monos, COX-2 was induced by IL-1A and IL-1B, but not IFN-g or IL-27. TLR 1-9 agonists induced COX-2, with TLR2/4/5 agonists being the strongest inducers. COX-2 induction by these factors was non-overlapping with PD-L1 induction in tumor cells and Monos, suggesting non-redundant pathways of immune resistance. PGE2 had context-dependent effects in Monos, depending on the cytokines, TLR agonists, and donors assayed: PGE2 increased VEGF secretion by resting Monos from 4/4 donors tested, but increased IL-6, IL-10 and TNF-a secretion in only 1/4 donors; PGE2 increased imiquimod-induced TNF-a secretion, but decreased LPS-induced TNF-a secretion. EP2 and EP4 inhibitors counteracted PGE2-mediated cytokine modulation, and showed synergistic effects when combined in the context of high dose of PGE2 (500nM). Additionally, PGE2 suppressed the in vitro generation of mature DCs, reducing CD80 and CD83 expression and increasing CD16.ConclusionsUnderstanding and preventing anti-PD-1 treatment resistance is a critical goal. Our results suggest that the COX-2/PGE2 pathway is expressed in tumor and immune cells, and modulates myeloid cell functions in a context-dependent manner. COX-2 expression is non-redundant with PD-L1 expression, providing a rationale to test COX-2 pathway inhibition in conjunction with anti-PD-1. Available drugs targeting this pathway, including IL-1R and IL-1B inhibitors, NSAIDs, and EP2 and EP4 inhibitors, will enable the clinical development of combination treatment regimens.AcknowledgementsWe gratefully acknowledge support from NCI R01-CA142779, Bristol Myers Squibb, and the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy.ReferencesDuffield AS, Ascierto ML, Anders RA, et al. The immunosuppressive tumor microenvironment (TME) in nasopharyngeal carcinoma: implications for immunotherapy. AACR 2018;Abstract 4750.Besharati S, McMiller T, Yarchoan M, et al. The immunosuppressive tumor microenvironment (TME) in epstein-barr virus (EBV)-positive and EBV-negative gastric cancers: implications for immunotherapy. SITC 2018;P541 (abstr).Taube JM, Young GD, McMiller TL, et al. Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade. Clin Cancer Res 2015;21:3969–76.Duffield AS, Ascierto ML, Anders RA, et al. Th17 immune microenvironment in epstein-barr virus negative Hodgkin lymphoma: implications for immunotherapy. Blood Advances 2017;1:1324–34.

scholarly journals IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Kewei Liu ◽  
Ai Huang ◽  
Jun Nie ◽  
Jun Tan ◽  
Shijie Xing ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint Blockade ◽  
Future Research ◽  
Barr Virus ◽  
Promote Tumor Growth ◽  
Epstein Barr ◽  
Mechanistic Basis ◽  
Tumor Growth And Metastasis

Interleukin-35 (IL-35) is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35 that has recently been shown to play diverse and important roles in the tumor microenvironment (TME). Owing to its immunosuppressive activity and ability to promote tumor growth and progression, IL-35 is widely recognized as a key mediator of TME status. Immune cells are key mediators of diverse tumor-related phenotypes, and immunosuppressive cytokines such as IL-35 can promote tumor growth and metastasis in TME. These influences should be considered together. Since tumor immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance, a new target or efficacy enhancing factor is urgently needed. Suppressing IL-35 production and activity has been demonstrated as an effective factor that inhibits tumor cells viability, and further investigation of this cytokine is warranted. However, the mechanistic basis for IL-35-mediated regulation of immune cells in the TME remains to be fully clarified. In the present review, we explore the roles of IL-35 in regulating immune cells within the TME. In addition, we highlight IL-35 as a specific immunological target and discuss its possible relevance in the context of immunotherapy. Lastly, we sought to summarize potential future research directions that may guide the advancement of current understanding regarding the role of this important cytokine as a regulator of oncogenesis.

Epstein-Barr Virus Status Correlates with Composition and Prognostic Impact of the Tumor Microenvironment in Classical Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 52-52
Author(s):  
Peter Kamper ◽  
Knud Bendix ◽  
Stephen Jacques Hamilton-Dutoit ◽  
Bent Honore ◽  
Francesco d'Amore
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Cell Marker ◽  
Classical Hodgkin Lymphoma ◽  
Barr Virus ◽  
Epstein Barr

Abstract Abstract 52 Background: Classical Hodgkin lymphoma (cHL) is often characterized by a minority of neoplastic cells surrounded by a heterogeneous background of reactive non-neoplastic cells. An increased amount of certain cell subsets, such as T-regulatory lymphocytes and macrophages, in the microenvironment of cHL tumor lesions has been found to correlate with an adverse prognosis, probably as a result of enhanced immune tolerance towards tumor cells. Furthermore, it has also been suggested that the presence of Epstein-Barr virus (EBV) infection in the Hodgkin Reed-Sternberg (HRS) cells, may modulate the composition of the tumor microenvironment. Aim: In the present study, we have analyzed the possible correlation between EBV-status, a number of tumor microenvironment parameters and outcome in a large retrospective series of newly diagnosed cHL patients. Design and Methods: A tissue microarray was constructed from paraffin embedded pre-therapeutic tumor tissue biopsies obtained from 288 newly diagnosed cHL cases. The expression in the tumor microenvironment of the macrophage markers CD68 and CD163, the regulatory T-cell marker FoxP3 and the cytotoxic T-cell marker Granzyme-B (GrB) was assessed by immunohistochemistry (IHC) using a previously described semi-automated stereological counting approach (Haematologica 2011;96:269–276). The presence of EBV in HRS cells was investigated using 'in situ' hybridization for EBV-encoded RNAs 1 and 2 and LMP-1 IHC. Clinical data were obtained from clinical records. The correlation between clinic-pathological features and EBV was assessed using the rank-sum or Kruskal-Wallis test. The impact of clinico-pathological parameters on event-free (EFS) and overall survival (OS) was evaluated using the log rank test. Results: The 288 patients had a median age of 37 yrs (range: 6–86 yrs). The M:F ratio was 1.3. One third (33%) of the patients were positive for EBV in the HRS cells. EBV-positive cases exhibited higher numbers of CD68 (p=0.001), CD163 (p=0.0002), GrB (p<0.0001), and FoxP3 (0.0009)-positive cells. Excluding cases of mixed cellularity from the analysis, the significant correlation between EBV and CD163 (p=0.03), GrB (p=0.003), FoxP3 (p=0.006) remained, whereas the correlation for CD68 was slightly weakened (p=0.06). In the entire cohort (n=288), a high expression of CD68, CD 163 and GrB were found to correlate with significantly lower OS and EFS (high vs. low CD68: 5-year OS, 73% vs. 87% p=0.002, 5-year EFS, 58% vs. 70% p=0.03; high vs. low CD163: 5-year OS, 78% vs. 87%, p=0.03, 5-year EFS, 62% vs. 69%, p= 0.04) and high GrB: 5-year OS, 77% vs 88 %, p=0.004, 5-year EFS, 61% vs. 69%, p= 0.02). Interestingly, the influence of tumor microenviromental parameters on outcome was more pronounced in EBV-negative cases (n=193) than in EBV-positive ones (n=95). In the former, significantly lower OS and EFS values were associated with a high expression of CD68 (high vs. low CD68: 5-year OS, 60% vs. 92%, 5-year EFS, 43% vs. 71%, both p<0.001), high CD163 (5-year OS, 72% vs. 89%, p<0.001, 5-year EFS, 58% vs. 69%, p= 0.03) and high GrB (5-year OS, 61% vs. 90%, 5-year EFS, 43%vs. 71%, both p<0.001). Among the EBV-positive cohort, the corresponding OS and EFS values were high CD68 (5-year OS, 85% vs. 82%, p=0.69, 5-year EFS, 72%vs. 66%, p=0.43), high CD163 (5-year OS, 86% vs. 84%, p=0.34, 5-year EFS, 67%vs. 71%, p=0.48) and high GrB (5-year OS, 88% vs. 81%, p=0.34, 5-year EFS, 73%vs. 65%, p= 0.63).The number of FoxP3-cells was not found to affect the prognosis in neither EBV-negative nor EBV-positive cases. Conclusions: The present study confirms that the EBV-status in cHL is associated with distinct features of the tumor microenvironment. As a novel finding, our results suggest that the prognostic impact of intratumoral reactive non-neoplastic cell subsets is EBV-status dependent, i.e. a significantly adverse impact of an increased amount of certain bystander cell subsets on outcome was only found in EBV-negative cases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tumor microenvironment contributes to Epstein-Barr virus anti-nuclear antigen-1 antibody production in nasopharyngeal carcinoma

2017 ◽  
Vol 14 (2) ◽  
pp. 2458-2462 ◽  
Author(s):  
Ping Ai ◽  
Zhiping Li ◽  
Yong Jiang ◽  
Changping Song ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Microenvironment ◽  
Antibody Production ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Modulation of the tumor microenvironment by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma

2018 ◽  
Vol 109 (2) ◽  
pp. 272-278 ◽  
Author(s):  
Tomokazu Yoshizaki ◽  
Satoru Kondo ◽  
Kazuhira Endo ◽  
Yosuke Nakanishi ◽  
Mitsuharu Aga ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Microenvironment ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Virus Latent Membrane Protein

scholarly journals Repertoire and frequency of immune cells reactive to Epstein-Barr virus–derived autologous lymphoblastoid cell lines

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1334-1343 ◽  
Author(s):  
Sumita Bhaduri-McIntosh ◽  
Marisa J. Rotenberg ◽  
Benjamin Gardner ◽  
Marie Robert ◽  
George Miller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Immune Cells ◽  
Epstein Barr Virus ◽  
Ex Vivo ◽  
Lymphoblastoid Cell Lines ◽  
Barr Virus ◽  
Different Types ◽  
Epstein Barr

AbstractAnswers to questions about frequency and repertoire of immune cells, relative contributions made by different types of immune cells toward the total Epstein-Barr virus (EBV)–directed response and the variation of such responses in healthy persons have been elusive because of disparities in assays, antigen presenting cells, and antigenic sources used in previous experiments. In this study, we addressed these questions using an assay that allowed direct comparison of responses generated by different types of cells of the immune system. This short-term (20-hour) ex vivo assay measured interferon-γ production by blood cells in response to autologous EBV-transformed lymphoblastoid cell lines (LCLs). Our experiments defined the variation in responses among persons and clearly distinguished 10 healthy EBV-immune from 10 healthy EBV-naive persons. In EBV-immune persons, 33% of responding cells were CD4+, 43.3% were CD8+, and 12.9% were γ-δ T cells. LCL-reactive CD8+ T cells were only 1.7-fold more frequent than similarly reactive CD4+T cells. Responses by γ-δ T cells were 6-fold higher in seropositive than in seronegative persons. Our findings emphasize the importance of CD4+ and γ-δ T-cell responses and have implications for immunotherapy and for identifying defects in T-cell populations that might predispose to development of EBV-associated lymphomas.

scholarly journals Tumor microenvironment composition in pediatric classical Hodgkin lymphoma is modulated by age and Epstein-Barr virus infection

2011 ◽  
Vol 131 (5) ◽  
pp. 1142-1152 ◽  
Author(s):  
Mário Henrique M. Barros ◽  
Gabriela Vera-Lozada ◽  
Fernando A. Soares ◽  
Gerald Niedobitek ◽  
Rocio Hassan
Keyword(s):  
Tumor Microenvironment ◽  
Virus Infection ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Classical Hodgkin Lymphoma ◽  
Barr Virus ◽  
Epstein Barr ◽  
Barr Virus Infection

scholarly journals Prognostic Value of Epstein-Barr Virus (EBV)-Induced Gene 3 (EBI3) in Diffuse Large B Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5411-5411
Author(s):  
Hong Zheng ◽  
Juan Huang
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Tumor Cells ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Epstein Barr ◽  
Large B Cell

Abstract Background: Epstein-Barr virus (EBV)-induced gene 3 (EBI3) as a subunit for heterodimeric cytokines IL-27 and IL-35, plays important roles both in regulation of T cell proliferation and Th1,Th2 and Th17 cells differentiation. EBI3 was closely related with tumor prognosis. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults with cure-rates of 40-60%. However, Relapse and refractory rate remain in 40% or so. In the present study, we aimed to detect the expression of EBI3 in DLBCL and to analyze its relationship with prognosis. Methods: We retrospective reviewed medical records of 51 newly diagnosed DLBCL patients in Sichuan People's Hospital between January 2010 and December 2016. Immunohistochemical (IHC) assay was used to detect the expression of EBI3 and PD-1 in DLBCL. The expression of CD5, CD30, Bcl-2, Bcl-6, C-myc and Epstein-Barr virus (EBV)-encoded RNAs (EBERs) in tumor specimens from 53 patients was also detected by IHC. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. Results: Of the 51 patients, 40 (78.4%) were EBI3-positive in tumor specimens. And PD-1 expression (39/40) was almost in parallel with EBI3 in tumor specimens. EBI3 expression was common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype. Patients with EBI3 expression in tumor were more likely to be resistant to first-line chemotherapy when compared with the patients without EBI3 expression in tumor microenvironment (P <0.05). EBI3 expression in tumor microenvironment was correlated with PD-1 expression (r = − 0.20, P = 0.04). Only one patient with EBI3 expression was no PD-1 expression. No correlations were detected between EBI3 expression and the expression of EBER as well as other markers: ALK, CD5, c-Myc and CD30. The complete remission (CR) rates were 7.5% (3/40) and 71.4% in patients with and without EBI3 expression in tumor cells (P = 0.02). EBI3 expression in tumor cells was an independent risk predictor for ORR (P < 0.05). Conclusions: Our results indicate that EBI3 associated with poor prognosis and EBI3 may be a potential therapeutic target and prognosis marker. Disclosures No relevant conflicts of interest to declare.

scholarly journals CAR-T cells and TRUCKs that recognize an EBNA-3C-derived epitope presented on HLA-B*35 control Epstein-Barr virus-associated lymphoproliferation

2020 ◽  
Vol 8 (2) ◽  
pp. e000736
Author(s):  
Anna Christina Dragon ◽  
Katharina Zimmermann ◽  
Thomas Nerreter ◽  
Deborah Sandfort ◽  
Julia Lahrberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Cells ◽  
Epstein Barr Virus ◽  
Target Cells ◽  
Barr Virus ◽  
Car T Cells ◽  
Car T ◽  
Epstein Barr

BackgroundImmunosuppressive therapy or T-cell depletion in transplant patients can cause uncontrolled growth of Epstein-Barr virus (EBV)-infected B cells resulting in post-transplant lymphoproliferative disease (PTLD). Current treatment options do not distinguish between healthy and malignant B cells and are thereby often limited by severe side effects in the already immunocompromised patients. To specifically target EBV-infected B cells, we developed a novel peptide-selective chimeric antigen receptor (CAR) based on the monoclonal antibody TÜ165 which recognizes an Epstein-Barr nuclear antigen (EBNA)−3C-derived peptide in HLA-B*35 context in a T-cell receptor (TCR)-like manner. In order to attract additional immune cells to proximity of PTLD cells, based on the TÜ165 CAR, we moreover generated T cells redirected for universal cytokine-mediated killing (TRUCKs), which induce interleukin (IL)-12 release on target contact.MethodsTÜ165-based CAR-T cells (CAR-Ts) and TRUCKs with inducible IL-12 expression in an all-in-one construct were generated. Functionality of the engineered cells was assessed in co-cultures with EBNA-3C-peptide-loaded, HLA-B*35-expressing K562 cells and EBV-infected B cells as PTLD model. IL-12, secreted by TRUCKs on target contact, was further tested for its chemoattractive and activating potential towards monocytes and natural killer (NK) cells.ResultsAfter co-cultivation with EBV target cells, TÜ165 CAR-Ts and TRUCKs showed an increased activation marker expression (CD137, CD25) and release of proinflammatory cytokines (interferon-γ and tumor necrosis factor-α). Moreover, TÜ165 CAR-Ts and TRUCKs released apoptosis-inducing mediators (granzyme B and perforin) and were capable to specifically lyse EBV-positive target cells. Live cell imaging revealed a specific attraction of TÜ165 CAR-Ts around EBNA-3C-peptide-loaded target cells. Of note, TÜ165 TRUCKs with inducible IL-12 showed highly improved effector functions and additionally led to recruitment of monocyte and NK cell lines.ConclusionsOur results demonstrate that TÜ165 CAR-Ts recognize EBV peptide/HLA complexes in a TCR-like manner and thereby allow for recognizing an intracellular EBV target. TÜ165 TRUCKs equipped with inducible IL-12 expression responded even more effectively and released IL-12 recruited additional immune cells which are generally missing in proximity of lymphoproliferation in immunocompromised PTLD patients. This suggests a new and promising strategy to specifically target EBV-infected cells while sparing and mobilizing healthy immune cells and thereby enable control of EBV-associated lymphoproliferation.

Epstein-Barr virus induces adipocyte dedifferentiation to modulate the tumor microenvironment

2021 ◽  
pp. canres.3121.2020
Author(s):  
Shu-Chen Liu ◽  
Ngan-Ming Tsang ◽  
Po-Ju Lee ◽  
Yun-Hua Sui ◽  
Chen-Han Huang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals 040 Acute cerebellar ataxia following epstein-barr virus infection

2019 ◽  
Vol 90 (e7) ◽  
pp. A14.1-A14
Author(s):  
Stephanie L Barnes ◽  
Bruce J Brew
Keyword(s):  
Cerebellar Ataxia ◽  
Infectious Mononucleosis ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
List Type ◽  
Retrospective Case ◽  
Barr Virus ◽  
Ebv Infection ◽  
Acute Cerebellar Ataxia ◽  
Epstein Barr

IntroductionInfectious aetiologies such as acute Epstein-Barr virus (EBV) infection are in the differential diagnosis for acute cerebellar ataxia (ACA). This syndrome remains exceptionally rare and not well characterised in adults.e.g. 1 2MethodsA retrospective case review of a patient diagnosed with ACA following EBV infection with implications for pathogenesis and treatment.ResultsA 29-year-old Caucasian male presented with a three day history of ACA. Seven days prior he was diagnosed with infectious mononucleosis; bloodwork was consistent with acute EBV infection. These symptoms improved rapidly with oral prednisolone. He took no regular medications, drank alcohol moderately and had no significant family history.On examination, he was afebrile, ataxic and mildly dysarthric. Sensory examination was normal, particularly proprioception. Romberg’s test was negative. Remaining neurological and general examination was normal.Bloodwork showed mild liver dysfunction and positive ANA (titre 1/320, homogenous and speckled patterns). Immune screen was otherwise negative. Antineuronal antibody panel was negative in serum and CSF. CSF glucose was 3.1 mmol/L, protein 751 mg/L, albumin 523 mg/L, neopterin 24 nmol/L and B2 microglobulin 1.1 mg/L. The sample was acellular with negative EBV PCR (<500 copies/mL). Other infective serology and PCRs were also negative. MRI brain with gadolinium showed no abnormality.The patient received supportive care and was neurologically normal within three months.ConclusionsACA related to EBV is rare in adults. This report is important because it documents an adult case, other ACA causes have been rigorously excluded, resolution without antiviral therapy is detailed, and investigations support an immune-mediated pathogenesis.ReferencesMcCarthy CL, McColgan P, Martin P. Acute cerebellar ataxia due to Epstein-Barr virus. Pract Neurol 2012;12:238–240.Lascelles RG, Longson M, Johnson PJ, Chiang A. Infectious mononucleosis presenting as acute cerebellar syndrome. Lancet 1973;2:707.

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