Genomic alterations underlying immune privilege in malignant lymphomas

Mottok, Anja

doi:10.1097/moh.0000000000000155

Cited by 19 publications

(7 citation statements)

References 147 publications

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“…genomic alterations 121 and altered cytokine/chemokine networks, 8,122 future studies must provide a more comprehensive link between genetic alterations and TME composition in cHL.…”

Section: Biomarker-driven Prognostication and Risk Stratification In Chlmentioning

confidence: 99%

Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

Mottok

Steidl

2018

Blood

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Hodgkin lymphoma is considered a prime example of treatment success, with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem-cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches. In recent years, many new therapeutic agents have emerged from preclinical and clinical studies that target molecular hallmarks of Hodgkin lymphoma, including the aberrant phenotype of the tumor cells, deregulated oncogenic pathways, and immune escape. The antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors have already shown great success in patients with relapsed/refractory disease, leading to US Food and Drug Administration approval and new trials testing these agents in various clinical settings. The expanding knowledge and understanding of Hodgkin lymphoma biology and disease progression, as well as the development of robust tools for biomarker-driven risk stratification and therapeutic decision making, continue to be fundamentally important for the success of these and other novel agents. We anticipate that the availability and clinical implementation of novel molecular assays will be instrumental in an era of rapid shifts in the treatment landscape of this disease. Here, we review the current knowledge of Hodgkin lymphoma pathobiology, highlighting the related development of novel treatment strategies and prognostic models that hold the promise to continually challenge and change the current standard of care in classical Hodgkin lymphoma.

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“…genomic alterations 121 and altered cytokine/chemokine networks, 8,122 future studies must provide a more comprehensive link between genetic alterations and TME composition in cHL.…”

Section: Biomarker-driven Prognostication and Risk Stratification In Chlmentioning

confidence: 99%

Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

Mottok

Steidl

2018

Blood

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“…PTL and PCNSL have lost HLA-DR in 61% and 46% of cases, respectively. 48 In contrast with other types of DLBCL, genetic lesions of MHC-II genes represent the main mechanism of HLA-DR loss: 48 , 49 MHC-II is mutated in 78% of PTL and 50% of PCNSL. 49 Transcription factors seem to be rarely implicated in HLA-II loss in PTL: CIITA and FOXP1 rearrangements are present in only 10% and 7% of cases, respectively.…”

Section: How Lymphoma May Hide From the Immune Systemmentioning

confidence: 99%

Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy

Charette

Houot

2018

Haematologica

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Evading immune eradication is a prerequisite for neoplastic progression and one of the hallmarks of cancer. Here, we review the different immune escape strategies of lymphoma and classify them into two main mechanisms. First, lymphoma cells may “hide” to become invisible to the immune system. This can be achieved by losing or downregulating MHC and/or molecules involved in antigen presentation (including antigen processing machinery and adhesion molecules), thereby preventing their recognition by the immune system. Second, lymphoma cells may “defend” themselves to become resistant to immune eradication. This can be achieved in several ways: by becoming resistant to apoptosis, by expressing inhibitory ligands that deactivate immune cells and/or by inducing an immunosuppressive (humoral and cellular) microenvironment. These immune escape mechanisms may have therapeutic implications. Their identification may be used to guide “personalized immunotherapy” for lymphoma.

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“…5 discoveries that linked somatic gene mutations with immune escape phenotypes 12,15,16 and emergence of breakthrough immunotherapies targeting microenvironment biology, such as immune checkpoint inhibition. [17][18][19][20] However, knowledge about somatic gene mutations underlying crosstalk of lymphoma cells with immune infiltrates and changes in microenvironment composition is very sparse. Proof of concept that microenvironment biology and immune privilege are important aspects of PMBCL pathogenesis was demonstrated in a previous study that established frequent alterations of CIITA, the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, to underlie loss of MHC class II expression in a subgroup of patients, a finding that correlated with a reduced number of cytotoxic T cells and T helper cells in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation

Viganò

Gunawardana

Mottok

et al. 2018

Blood

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Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma thought to arise from thymic medullary B cells. Gene mutations underlying the molecular pathogenesis of the disease are incompletely characterized. Here, we describe novel somatic mutations in 15 of 62 primary cases of PMBCL (24.2%) and in all PMBCL-derived cell lines tested. The majority of mutations (11/21; 52%) were hotspot single nucleotide variants in exon 8, leading to an I242N amino acid change in the transmembrane domain. Functional analyses establish this mutation as gain of function leading to constitutive activation of the JAK-STAT pathway and upregulation of downstream cytokine expression profiles and B cell-specific antigens. Moreover, expression of I242N mutant IL4R in a mouse xenotransplantation model conferred growth advantage in vivo. The pattern of concurrent mutations within the JAK-STAT signaling pathway suggests additive/synergistic effects of these gene mutations contributing to lymphomagenesis. Our data establish mutations as novel driver alterations and provide a strong preclinical rationale for therapeutic targeting of JAK-STAT signaling in PMBCL.

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Genomic alterations underlying immune privilege in malignant lymphomas

Cited by 19 publications

References 147 publications

Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy

Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation

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