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Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay among transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs (FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2) bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remains unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac, HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (heptad, PU.1, CTCF, STAG2) in HSPC subsets (stem/multipotent progenitors plus common myeloid, granulocyte macrophage, and megakaryocyte erythrocyte progenitors) and found TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs, including PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of TF complexes was at least partially regulated by features encoded in DNA sequence motifs. Taken together, this study comprehensively characterizes the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying data sets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analyzing aberrant regulatory networks in leukemic cells.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Células Madre Hematopoyéticas , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Células Madre Hematopoyéticas/metabolismo , Regulación de la Expresión Génica , Hematopoyesis/genética , Cromatina/metabolismoRESUMEN
Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.
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Infecciones por Virus de Epstein-Barr , Enfermedad de Hodgkin , Linfoma no Hodgkin , Linfoma , Trastornos Linfoproliferativos , Humanos , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/patología , Microambiente TumoralRESUMEN
Radiotherapy is routinely used for management of limited-stage follicular lymphoma (FL), yet half of patients ultimately relapse. We hypothesized that the presence of specific gene mutations may predict outcomes. We performed targeted sequencing of a 69-gene panel in 117 limited-stage FL patients treated with radiotherapy and identified recurrently mutated genes. CREBBP was most frequently mutated, and mutated CREBBP was associated with inferior progression-free survival, though not after false discovery rate adjustment. This association failed to validate in an independent cohort. We conclude that recurrent gene mutations do not predict outcomes in this setting. Alternative biomarkers may offer better prognostic insight.
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T-cell-engaging bispecific antibodies (T-BsAb) have produced impressive clinical responses in patients with relapsed/refractory B-cell malignancies, although treatment failure remains a major clinical challenge. Growing evidence suggests that a complex interplay between immune cells and tumor cells is implicated in the mechanism of action and therefore, understanding immune regulatory mechanisms might provide a clue for how to improve the efficacy of T-BsAb therapy. Here, we investigated the functional impact of regulatory T (Treg) cells on anti-tumor immunity elicited by T-BsAb therapy. In a preclinical model of myeloma, the activation and expansion of Treg cells in the bone marrow were observed in response to anti-B-cell maturation antigen (BCMA) T-BsAb therapy. T-BsAb triggered the generation of induced Treg cells from human conventional CD4 cells after co-culture with tumor cells. Moreover, T-BsAb directly activated freshly isolated circulating Treg cells, leading to the production of interleukin-10 and inhibition of T-BsAb-mediated CD8 T-cell responses. The activation of Treg cells was also seen in bone marrow samples from myeloma patients after ex vivo treatment with T-BsAb, further supporting that T-BsAb have an impact on Treg homeostasis. Importantly, transient ablation of Treg cells in combination with T-BsAb therapy dramatically improved effector lymphocyte activities and disease control in the preclinical myeloma model, leading to prolonged survival. Together, this information suggests that therapy-induced activation of Treg cells critically regulates anti-tumor immunity elicited by T-BsAb therapy, with important implications for improving the efficacy of such treatment.
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Anticuerpos Biespecíficos , Mieloma Múltiple , Humanos , Linfocitos T Reguladores , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivosRESUMEN
T-cell-engaging bispecific antibody (T-BsAb, also known as BiTE) therapy has emerged as a powerful therapeutic modality against multiple myeloma. Given that T-BsAb therapy redirects endogenous T cells to eliminate tumor cells, reinvigorating dysfunctional T cells may be a potential approach to improve the efficacy of T-BsAb. While various immunostimulatory cytokines can potentiate effector T-cell functions, the optimal cytokine treatment for T-BsAb therapy is yet to be established, partly due to a concern of cytokine release syndrome driven by aberrant interferon (IFN)-γ production. Here, we functionally screen immunostimulatory cytokines to determine an ideal combination partner for T-BsAb therapy. This approach reveals interleukin (IL)-21 as a potential immunostimulatory cytokine with the ability to augment T-BsAb-mediated release of granzyme B and perforin, without increasing IFN-γ release. Transcriptome profiling and functional characterization strongly support that IL-21 selectively targets the cytotoxic granule exocytosis pathway, but not pro-inflammatory responses. Notably, IL-21 modulates multiple steps of cytotoxic effector functions including upregulation of co-activating CD226 receptor, increasing cytotoxic granules, and promoting cytotoxic granule delivery at the immunological synapse. Indeed, T-BsAb-mediated myeloma killing is cytotoxic granule-dependent, and IL-21 priming significantly augments cytotoxic activities. Furthermore, in vivo IL-21 treatment induces cytotoxic effector reprogramming in bone marrow T cells, showing synergistic anti-myeloma effects in combination with T-BsAb therapy. Together, harnessing the cytotoxic granule exocytosis pathway by IL-21 may be a potential approach to achieve better responses by T-BsAb therapy.
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Anticuerpos Biespecíficos , Exocitosis , Mieloma Múltiple , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Humanos , Ratones , Animales , Mieloma Múltiple/inmunología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Mieloma Múltiple/patología , Citotoxicidad Inmunológica , Interleucinas/metabolismo , Línea Celular Tumoral , Citocinas/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Granzimas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacosRESUMEN
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.
RESUMEN
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.
RESUMEN
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.
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Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Leucemia Linfocítica Crónica de Células B , Melanoma , Receptor de Muerte Celular Programada 1 , Neoplasias Cutáneas , Humanos , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Progresión de la Enfermedad , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Melanoma/tratamiento farmacológico , Melanoma/etiología , Melanoma/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antineoplásicos/inmunología , Antineoplásicos/uso terapéuticoRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma seen in clinical practice. Despite huge strides in understanding its biology, front-line therapy has remained unchanged for decades. Roughly one-third of patients have primary refractory or relapse following the end of conventional first-line therapy. The outcome of patients with primary refractory disease and those with early relapse (defined as relapse less than 1 year from the end of therapy) is markedly inferior to those with later relapse and is exemplified by dismal overall survival. In this article, the authors term patients with features that identify them as being at particularly high-risk for either primary refractory disease or early relapse, as 'ultra-high-risk'. As new treatment options become established (e.g. bispecific T-cell engagers, chimeric antigen receptor 'CAR' T-cells and antibody-drug conjugates), it is likely that there will be a push to incorporate some of these agents into the first-line setting for patients identified as ultra-high-risk. In this review, the authors outline advances in positron emission tomography, widely available laboratory assays and clinical prognosticators, which can detect a high proportion of patients with ultra-high-risk disease. Since these approaches are pragmatic and able to be adopted widely, they could be incorporated into routine clinical practice.
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Linfoma de Células B Grandes Difuso , Recurrencia Local de Neoplasia , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/terapiaRESUMEN
Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.
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Células Asesinas Naturales/inmunología , Metabolismo de los Lípidos/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Microambiente Tumoral/inmunología , Animales , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Células Asesinas Naturales/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Potencial de la Membrana Mitocondrial/genética , Potencial de la Membrana Mitocondrial/inmunología , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , PPAR gamma/genética , PPAR gamma/inmunología , Microambiente Tumoral/genéticaRESUMEN
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).
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Infecciones por Virus de Epstein-Barr , Linfoma no Hodgkin , Trastornos Linfoproliferativos , Adenina/análogos & derivados , Sistema Nervioso Central , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Herpesvirus Humano 4 , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/etiología , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Piperidinas , Linfocitos TRESUMEN
Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.
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Antígenos CD/fisiología , Inhibidores de Puntos de Control Inmunológico , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma Folicular/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Terapia Molecular Dirigida , Proteínas de Neoplasias/fisiología , Antígenos CD/biosíntesis , Antígenos CD/genética , Linfocitos B/metabolismo , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Linfocitos Infiltrantes de Tumor/metabolismo , Linfoma de Células B de la Zona Marginal/genética , Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Síndrome , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
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Adenina/análogos & derivados , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/mortalidad , Linfoma/tratamiento farmacológico , Linfoma/mortalidad , Piperidinas/administración & dosificación , Adenina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
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.
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Antígeno B7-H1/metabolismo , Infecciones por Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , ARN Viral/metabolismo , Antígeno B7-H1/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/genética , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/virología , MicroARNs/genética , Proteínas de Neoplasias/genética , Proteína 2 Ligando de Muerte Celular Programada 1/genética , ARN Viral/genéticaRESUMEN
Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163+ monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3-CD56hiCD16-ve NK cells had substantially higher PD-1 expression relative to CD3-CD56dimCD16+ cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163+ monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m2, bleomycin 10 000 IU/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m2, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1hi NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3-CD56hiCD16-ve NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3-CD56hiCD16-ve NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.
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Antígeno B7-H1/inmunología , Enfermedad de Hodgkin/inmunología , Células Asesinas Naturales/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Macrófagos/inmunología , Modelos Inmunológicos , Monocitos/inmunología , Proteínas de Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Escape del Tumor , Adulto , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Células Asesinas Naturales/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Macrófagos/patología , Masculino , Monocitos/patología , Prednisona/administración & dosificación , Rituximab , Vinblastina/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B-cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion. The tumour microenvironment is manipulated by PMBCL tumours to avoid T-cell mediated destruction via strategies that include loss of tumour cell antigenicity, T-cell exhaustion and activation of suppressive T-regulatory cells. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and DA-EPOCH-R (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) are the most common first-line immunochemotherapy regimens. End of treatment positron emission tomography scans are the recommended imaging modality and are being evaluated to stratify patients for radiotherapy. Relapsed/refractory disease has a relatively poor outcome despite salvage immunochemotherapy and subsequent autologous stem cell transplantation. Novel therapies are therefore being developed for treatment-resistant disease, targeting aberrant cellular signalling and immune evasion.