15 results on '"Sabdia MB"'
Search Results
2. Intra-tumoral and peripheral blood TIGIT and PD-1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma.
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Gunawardana J, Law SC, Sabdia MB, Fennell É, Hennessy A, Leahy CI, Murray PG, Bednarska K, Brosda S, Trotman J, Berkahn L, Zaharia A, Birch S, Burgess M, Talaulikar D, Lee JN, Jude E, Hawkes EA, Jain S, Nath K, Snell C, Swain F, Tobin JWD, Keane C, Shanavas M, Blyth E, Steidl C, Savage K, Farinha P, Boyle M, Meissner B, Green MR, Vega F, and Gandhi MK
- Abstract
In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)
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- 2024
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3. The IRE1α-endonuclease plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within Natural Killer cells in Hodgkin Lymphoma.
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Bednarska K, Thillaiyampalam G, Mujaj S, Nourse J, Gunawardana J, Sabdia MB, Law SC, Pilaar A, Cui Q, de Long LM, Vari F, Gandhi MK, and Cristino AS
- Abstract
Introduction: Hodgkin Lymphoma (HL) is deficient in Major Histocompatibility Complex-class I, rendering it susceptible to anti-tumoral immunity by Natural Killer (NK)-cells. Despite the functional impairment of PD-1+ NK-cells in HL, the underlying mechanisms of NK-cell dysfunction remain unclear., Methods: This study involved 14 HL patients and SNK10/KHYG-1 cell lines to assess NK-cell activation against cancer cells. Activation was measured through transcript (PCR) and protein expression (flow cytometry). Regulatory mechanisms associated with IRE1α activation were validated through knock-down and luciferase reporter assays., Results: Our findings reveal a novel role for IRE1α-endonuclease in fine-tuning NK-cell effector functions by orchestrating the XBP1s/microRNA-34a-5p/PD-1 axis. When NK-cells encounter cancer cells, IRE1α-endonuclease activates the decay of microRNA-34a-5p, resulting in increased expression of XBP1s and PD-1. IRE1α-endonuclease activation enhances NK-cells function while promoting PD-1 expression. In turn, PD-1 is directly regulated by microRNA-34a-5p, which binds to the 3'UTR of PD-1 transcript to repress PD-1 protein on the NK-cell surface. Importantly, IRE1α-pathway activation is impaired in NK-cells from HL patients., Conclusion: The IRE1α-endonuclease emerges as a key player, simultaneously regulating the XBP1s/microRNA-34a-5p/PD-1 axis in NK-cells, a process disrupted in HL. Targeting the IRE1α-pathway holds promise as a therapeutic strategy to optimise NK-cell functions in Hodgkin Lymphoma treatments., (S. Karger AG, Basel.)
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- 2024
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4. Inhibition of CD39 unleashes macrophage antibody-dependent cellular phagocytosis against B-cell lymphoma.
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Casey M, Segawa K, Law SC, Sabdia MB, Nowlan B, Salik B, Lee C, Winterford C, Pearson S, Madore J, Dougall WC, Gandhi MK, and Nakamura K
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- Humans, Rituximab pharmacology, Rituximab therapeutic use, Adenosine metabolism, Phagocytosis, Macrophages, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Redirection of tumor-associated macrophages to eliminate tumor cells holds great promise for overcoming therapeutic resistance to rituximab and other antibody drugs. Here, we determined the expression of ectonucleotidases CD39 and CD73 in diffuse large B-cell lymphoma (DLBCL), and examined the impact of extracellular ATP (eATP) metabolism on macrophage-mediated anti-lymphoma immunity. Immunostaining of tissue microarray samples showed that CD39 (the ecto-enzyme for eATP hydrolysis) was highly expressed in tumors with the non-germinal center B-cell-like (non-GCB) subtype, and to a lesser extent tumors with the GCB subtype. By contrast, the expression of CD73 (the ecto-enzyme for adenosine generation) was undetectable in tumor cells. Pharmacological blockade of CD39 prevented eATP degradation and enhanced engulfment of antibody-coated lymphoma cells by macrophages in a P2X7 receptor-dependent manner, indicating that eATP fueled antibody-dependent cellular phagocytosis (ADCP) activity. Importantly, inhibition of CD39 augmented in vivo anti-lymphoma effects by therapeutic antibodies including rituximab and daratumumab. Furthermore, the addition of a CD39 inhibitor to anti-CD20 and anti-CD47 combination therapy significantly improved survival in a disseminated model of aggressive B-cell lymphoma, supporting the benefit of dual targeting CD39-mediated eATP hydrolysis and CD47-mediated "don't eat me" signal. Together, preventing eATP degradation may be a potential approach to unleash macrophage-mediated anti-lymphoma immunity., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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5. Resolution of Melanoma to Programmed Death-1 Blockade but Simultaneous Rapid Progression of Concomitant Chronic Lymphocytic Leukemia.
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Burgess M, Keane C, Tobin JW, Law SC, Griffin A, Gill D, Ewing AD, Atkinson V, Mollee P, Sabdia MB, Saunders NA, and Gandhi MK
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- Humans, CTLA-4 Antigen antagonists & inhibitors, CTLA-4 Antigen immunology, Disease Progression, B7-H1 Antigen, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Melanoma drug therapy, Melanoma etiology, Melanoma pathology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Skin Neoplasms drug therapy, Skin Neoplasms etiology, Skin Neoplasms pathology, Immune Checkpoint Inhibitors immunology, Immune Checkpoint Inhibitors therapeutic use, Antineoplastic Agents immunology, Antineoplastic Agents therapeutic use
- Abstract
Here, we present a novel case of a patient with chronic lymphocytic leukemia (CLL) who received CTLA-4 and then PD-1 immune-checkpoint blockade (ICB) as treatment for concomitant metastatic melanoma. Whereas the metastatic melanoma was responsive to ICB, the CLL rapidly progressed (but responded to ICB cessation and ibrutinib). There were no new genetic mutational drivers to explain the altered clinical course. PD-1/PD-L1/PD-L2 and CTLA-4/CD80/CD86 expression was not increased in CLL B cells, CD8+ or CD4+ T-cell subsets, or monocytes. The patient's CLL B cells demonstrated strikingly prolonged in vitro survival during PD-1 blockade, which was not observed in samples taken before or after ICB, or with other patients. To our knowledge, a discordant clinical course to ICB coupled with these biological features has not been reported in a patient with dual malignancies., (© 2022 The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2023
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6. Neoantigens - the next frontier in precision immunotherapy for B-cell lymphoproliferative disorders.
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Sabdia MB, Patch AM, Tsang H, and Gandhi MK
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- Humans, Antigens, Neoplasm, Immune Checkpoint Inhibitors, Immunotherapy, Peptides, Immunologic Factors, HLA Antigens, Receptors, Antigen, B-Cell genetics, Neoplasms therapy, Lymphoproliferative Disorders
- Abstract
Broad activation of host T-cell immunity by immune checkpoint blockade, has revolutionized the treatment of some but not all B-cell lymphoproliferative disorders (LPDs). The challenge for next generation immunotherapeutics, is to successfully induce anti-tumor specific T-cell immunity across a range of B-LPDs, without provoking immune-related adverse events. An emerging strategy is to target neoantigens. Neoantigens are immunogenic peptides, unique to malignant cells, that are presented to T-cells via human leukocyte antigens. Neoantigens most commonly arise from non-synonymous mutations but can also be derived from tumor specific alterations along the protein biosynthesis pathway. B-cell LPDs uniquely express a clonal B-cell receptor (BCR) idiotype, consisting of immunoglobulin genes that undergo recombination and somatic hypermutation. Notably, the BCR idiotype can also give rise to 'immunoglobulin neoantigens'. Here, we provide an overview of current strategies to identify and validate immunoglobulin and non-immunoglobulin neoantigens as well as summarizing studies investigating neoantigens within B-cell LPDs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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7. Intratumoral T-cell receptor repertoire is predictive of interim PET scan results in patients with diffuse large B-cell lymphoma treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy.
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Shanavas M, Law SC, Hertzberg M, Hicks RJ, Seymour JF, Li Z, Merida de Long L, Nath K, Sabdia MB, Gunawardana J, Gandhi MK, and Keane C
- Abstract
Objectives: A diverse intratumoral T-cell receptor (TCR) repertoire is associated with improved survival in diffuse large B-cell lymphoma (DLBCL) treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy. We explored the impact of intratumoral TCR repertoire on interim PET (iPET) done after four cycles of R-CHOP, the relationships between intratumoral and circulating repertoire, and the phenotypes of expanded clonotypes., Methods: We sequenced the third complementarity-determining region of TCRβ in tumor samples, blood at pre-therapy and after four cycles of R-CHOP in 35 patients enrolled in ALLGNHL21 trial in high-risk DLBCL. We correlated the TCR diversity metrics with iPET status, gene expression profiles and HLA-class I genotypes. We then sequenced the FACS-sorted peripheral blood T cells in six patients, and pentamer-sorted EBV-specific CD8
+ T cells in one patient from this cohort., Results: Compared with iPET- patients, the intratumoral TCR repertoire in iPET+ patients was characterised by higher cumulative frequency of abundant clonotypes and higher productive clonality. There was a variable overlap between circulating and intratumoral repertoires, with the dominant intratumoral clonotypes more likely to be detected in the blood. The majority of shared clonotypes were CD8+ PD-1HI T cells, and CD8+ T cells had the largest clonal expansions in tumor and blood. In a patient with EBV+ DLBCL, EBV-specific intratumoral clonotypes were trackable in the blood., Conclusion: This study demonstrates that clonally expanded intratumoral TCR repertoires are associated with iPET+ and that the blood can be used to track tumor-associated antigen-specific clonotypes. These findings assist the rationale design and therapeutic monitoring of immunotherapeutic strategies in DLBCL., Competing Interests: CK has received consultancy fees, honoraria and or research funding from Bristol‐Myers Squibb, Celgene, Gilead Sciences, Janssen‐Cilag, MSD Oncology and Roche. MKG has received consultancy fees, honoraria and or research funding from Amgen, Bristol‐Myers Squibb, Celgene, Genentech, Gilead Sciences, Janssen‐Cilag, Merck Sharp & Dohme and Roche. JFS has received consultancy fees, honoraria and or research funding from AbbVie, Astra Zeneca, Celgene, Genentech, Gilead Sciences, Janssen‐Cilag, Mei Pharma, Morphosys, Roche, Sunesis and Takeda. The remaining authors declare no competing financial interests., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)- Published
- 2021
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8. Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.
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Law SC, Hoang T, O'Rourke K, Tobin JWD, Gunawardana J, Loo-Oey D, Bednarska K, Merida de Long L, Sabdia MB, Hapgood G, Blyth E, Clancy L, Hennig S, Keane C, and Gandhi MK
- Subjects
- Adenine analogs & derivatives, Central Nervous System, Herpesvirus 4, Human, Humans, Piperidines, T-Lymphocytes, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections drug therapy, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin etiology, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders etiology
- Abstract
Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291)., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)
- Published
- 2021
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9. Intratumoral T cells have a differential impact on FDG-PET parameters in follicular lymphoma.
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Nath K, Law SC, Sabdia MB, Gunawardana J, de Long LM, Sester D, Shanavas M, Tsang H, Tobin JWD, Halliday SJ, Hernandez A, Cross D, Bird RJ, Jain S, Keane C, Talaulikar D, Trotman J, Law P, and Gandhi MK
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- Humans, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Retrospective Studies, Fluorodeoxyglucose F18, Lymphoma, Follicular diagnostic imaging, Lymphoma, Follicular therapy
- Abstract
Data on the prognostic impact of pretherapy 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in follicular lymphoma (FL) is conflicting. The predictive utility of pretherapy total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) on outcome appears to vary between regimens. Chemoimmunotherapies vary in the extent of T-cell depletion they induce. The role of intratumoral T cells on pretherapy FDG-PET parameters is undefined. We assessed pretherapy FDG-PET parameters and quantified intratumoral T cells by multiple methodologies. Low intratumoral T cells associated with approximately sixfold higher TMTV, and FL nodes from patients with high TMTV showed increased malignant B-cell infiltration and fewer clonally expanded intratumoral CD8+ and CD4+ T-follicular helper cells than those with low TMTV. However, fluorescently labeled glucose uptake was higher in CD4+ and CD8+ T cells than intratumoral B cells. In patients with FDG-PET performed prior to excisional biopsy, SUVmax within the subsequently excised node associated with T cells but not B cells. In summary, TMTV best reflects the malignant B-cell burden in FL, whereas intratumoral T cells influence SUVmax. This may contribute to the contradictory results between the prognostic role of different FDG-PET parameters, particularly between short- and long-term T-cell-depleting chemoimmunotherapeutic regimens. The impact of glucose uptake in intratumoral T cells should be considered when interpreting pretherapy FDG-PET in FL., (© 2021 by The American Society of Hematology.)
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- 2021
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10. EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.
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Gandhi MK, Hoang T, Law SC, Brosda S, O'Rourke K, Tobin JWD, Vari F, Murigneux V, Fink L, Gunawardana J, Gould C, Oey H, Bednarska K, Delecluse S, Trappe RU, Merida de Long L, Sabdia MB, Bhagat G, Hapgood G, Blyth E, Clancy L, Wight J, Hawkes E, Rimsza LM, Maguire A, Bojarczuk K, Chapuy B, and Keane C
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- Adult, Aged, Aged, 80 and over, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms virology, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections virology, Female, Herpesvirus 4, Human isolation & purification, Humans, Immune Tolerance, Lymphoma etiology, Male, Middle Aged, Mutation, Transcriptome, Tumor Microenvironment, Central Nervous System Neoplasms etiology, Central Nervous System Neoplasms immunology, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections immunology, Herpesvirus 4, Human immunology, Lymphoma virology
- Abstract
Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment., (© 2021 by The American Society of Hematology.)
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- 2021
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11. Genetic aberrations of NLRC5 are associated with downregulated MHC-I antigen presentation and impaired T-cell immunity in follicular lymphoma.
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Gunawardana J, Lee JN, Bednarska K, Murigneux V, de Long LM, Sabdia MB, Birch S, Tobin JWD, and Gandhi MK
- Abstract
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Twenty to twenty-five percent of FL patients have progression of disease within 24 months. These patients may benefit from immunotherapy if intact antigen presentation is present. Molecular mechanisms impairing major histocompatibility complex class-I (MHC-I) in FL remain undefined. Here, by sequencing of 172 FL tumours, we found the MHC-I transactivator NLRC5 was the most frequent gene abnormality in the MHC-I pathway. Pyrosequencing showed that epigenetic silencing of the NLRC5 promoter occurred in 30% of cases and was mutually exclusive to copy number loss (CNL) in NLRC5 (∼6% of cases). Hypermethylation and CNLs (" NLRC5 aberrant") had reduced NLRC5 gene expression compared to wild-type (WT) cases. By NanoString, there was reduced gene expression of the MHC-I pathway in aberrant tissues, including immunoproteasome components ( PSMB8 and PSMB9) , peptide transporters of antigen processing ( TAP1 ), and MHC-I ( HLA-A ), compared to WT. By immunofluorescent microscopy, fewer NLRC5 protein-expressing malignant B-cells were observed in NLRC5 aberrant tissue sections compared to NLRC5 WT ( P < .01). Consistent with a pivotal role in the activation of CD8
+ T-cells, both CD8 and CD137 strongly correlated with NLRC5 expression (both r > 0.7; P < .0001). Further studies are required to determine whether patients with aberrant NLRC5 have a diminished response to immunotherapy., Competing Interests: The authors declare no competing financial interests., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2020
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12. Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma.
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Bararia D, Hildebrand JA, Stolz S, Haebe S, Alig S, Trevisani CP, Osorio-Barrios F, Bartoschek MD, Mentz M, Pastore A, Gaitzsch E, Heide M, Jurinovic V, Rautter K, Gunawardana J, Sabdia MB, Szczepanowski M, Richter J, Klapper W, Louissaint A Jr, Ludwig C, Bultmann S, Leonhardt H, Eustermann S, Hopfner KP, Hiddemann W, von Bergwelt-Baildon M, Steidl C, Kridel R, Tobin JWD, Gandhi MK, Weinstock DM, Schmidt-Supprian M, Sárosi MB, Rudelius M, Passerini V, Mautner J, and Weigert O
- Subjects
- Animals, Antigens, Differentiation, B-Lymphocyte metabolism, Cytokines metabolism, Histocompatibility Antigens Class II metabolism, Humans, Immunosuppression Therapy, Lymphoma, Follicular pathology, Mice, Antigen Presentation immunology, Cathepsins metabolism, Lymphoma, Follicular metabolism, Tumor Microenvironment immunology
- Abstract
Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4
+ T cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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13. LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma.
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Keane C, Law SC, Gould C, Birch S, Sabdia MB, Merida de Long L, Thillaiyampalam G, Abro E, Tobin JW, Tan X, Xu-Monette ZY, Young KH, Gifford G, Gabreilli S, Stevenson WS, Gill A, Talaulikar D, Jain S, Hernandez A, Halliday SJ, Bird R, Cross D, Hertzberg M, and Gandhi MK
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- Antigens, CD, CD8-Positive T-Lymphocytes, Hepatitis A Virus Cellular Receptor 2, Humans, Lymphocytes, Tumor-Infiltrating, Tumor Microenvironment, Lymphocyte Activation Gene 3 Protein, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators., (© 2020 by The American Society of Hematology.)
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- 2020
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14. EBV microRNA-BHRF1-2-5p targets the 3'UTR of immune checkpoint ligands PD-L1 and PD-L2.
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Cristino AS, Nourse J, West RA, Sabdia MB, Law SC, Gunawardana J, Vari F, Mujaj S, Thillaiyampalam G, Snell C, Gough M, Keane C, and Gandhi MK
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- B7-H1 Antigen genetics, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections pathology, Herpesvirus 4, Human genetics, Humans, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse virology, MicroRNAs genetics, Neoplasm Proteins genetics, Programmed Cell Death 1 Ligand 2 Protein genetics, RNA, Viral genetics, B7-H1 Antigen metabolism, Epstein-Barr Virus Infections metabolism, Herpesvirus 4, Human metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, MicroRNAs metabolism, Neoplasm Proteins metabolism, Programmed Cell Death 1 Ligand 2 Protein metabolism, RNA, Viral metabolism
- Abstract
Epstein-Barr virus-positive (EBV+) diffuse large B-cell lymphomas (DLBCLs) express high levels of programmed death ligand 1 (PD-L1) and PD-L2. MicroRNA (miR) regulation is an important mechanism for the fine-tuning of gene expression via 3'-untranslated region (3'UTR) targeting, and we have previously demonstrated strong EBV miR expression in EBV+ DLBCL. Whereas the EBV latent membrane protein-1 (LMP1) is known to induce PD-L1/L2, a potential counterregulatory role of EBV miR in the fine-tuning of PD-L1/L2 expression remains to be established. To examine this, a novel in vitro model of EBV+ DLBCL was developed, using the viral strain EBV WIL, which unlike common laboratory strains retains intact noncoding regions where several EBV miRs reside. This enabled interrogation of the relationship among EBV latency genes, cell of origin (COO), PD-L1, PD-L2, and EBV miRs. The model successfully recapitulated the full spectrum of B-cell differentiation, with 4 discrete COO phases: early and late germinal center B cells (GCBs) and early and late activated B cells (ABCs). Interestingly, PD-L1/L2 levels increased markedly during transition from late GCB to early ABC phase, after LMP1 upregulation. EBV miR-BamHI fragment H rightward open reading frame 1 (BHRF1)-2-5p clustered apart from other EBV miRs, rising during late GCB phase. Bioinformatic prediction, together with functional validation, confirmed EBV miR-BHRF1-2-5p bound to PD-L1 and PD-L2 3'UTRs to reduce PD-L1/L2 surface protein expression. Results indicate a novel mechanism by which EBV miR-BHRF1-2-5p plays a context-dependent counterregulatory role to fine-tune the expression of the LMP1-driven amplification of these inhibitory checkpoint ligands. Further identification of immune checkpoint-targeting miRs may enable potential novel RNA-based therapies to emerge., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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15. Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma.
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Cui Q, Vari F, Cristino AS, Salomon C, Rice GE, Sabdia MB, Guanzon D, Palma C, Mathew M, Talaulikar D, Jain S, Han E, Hertzberg MS, Gould C, Crooks P, Thillaiyampalam G, Keane C, and Gandhi MK
- Abstract
MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL), where they reflect the malignant B-cells and the immune infiltrate within the tumor microenvironment. There remains a paucity of data in DLBCL regarding cell-free (c-f) miRNA as disease response biomarkers. Immunosuppressive monocyte/macrophages, which are enriched in DLBCL, are disease response markers in DLBCL, with miRNA key regulators of their immunosuppressive function. Our aim was to determine whether plasma miRNA that reflect the activity of the malignant B-cell and/or immunosuppressive monocytes/macrophages, have value as minimally-invasive disease response biomarkers in DLBCL. Quantification of 99 DLBCL tissues, to select miRNA implicated in immunosuppressive monocytes/macrophage biology, found miR-494 differentially elevated. In a discovery cohort (22 patients), pre-therapy c-f miR-494 and miR-21 but not miR-155 were raised relative to healthy plasma. Both miR-494 and miR-21 levels 3-6 months reduced post immuno-chemotherapy. The validation cohort (56 patients) was from a prospective clinical trial. Interestingly, in sequential samples both miRNAs decreased in patients becoming Positron Emission Tomography/Computerized Tomography (PET/CT)-ve, but not in those remaining interim-PET/CT+. Patient monocytes were phenotypically and functionally immunosuppressive with ex-vivo monocyte depletion enhancing T-cell proliferation in patient but not healthy samples. Pre-therapy monocytes showed an immunosuppressive transcriptome and raised levels of miR-494. MiR-494 was present in all c-f nanoparticle fractions but was most readily detectable in unfractionated plasma. Circulating c-f miR-494 and miR-21 are disease response biomarkers with differential response stratified by interim-PET/CT in patients with DLBCL. Further studies are required to explore their manipulation as potential therapeutic targets., Competing Interests: CONFLICTS OF INTEREST The authors declare that no competing financial interests exists.
- Published
- 2018
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