Role of the tumor microenvironment in mature B-cell lymphoid malignancies

Fowler, Nathan; Cheah, Chan Yoon; Gascoyne, Randy D.; Gribben, John G.; Neelapu, Sattva S.; Ghia, Paolo; Bollard, Catherine M.; Ansell, Stephen M.; Curran, Michael A.; Wilson, Wyndham H.; O’Brien, Susan; Grant, Clíona; Little, Richard F.; Zenz, Thorsten; Nastoupil, Loretta J.; Dunleavy, Kieron

doi:10.3324/haematol.2015.139493

Cited by 81 publications

(65 citation statements)

References 147 publications

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“…19 Furthermore, substantially higher clonal T-cell responses were observed in EBV -pos vs EBV -neg DLBCL. 19 Although the prognostic impact of the TME in de novo DLBCL is well-established, [20][21][22][23][24] it remains untested as to whether the TME is associated with differential survival in EBV -pos DLBCL.…”

Section: Introductionmentioning

confidence: 99%

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Keane

Tobin

Gunawardana

et al. 2019

European J of Haematology

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ObjectiveEpstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBV‐pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno‐chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV‐neg DLBCL is well‐established, it remains untested whether the TME influences survival in EBV‐pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME).MethodsWe used the NanoString™ platform in a population‐based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL.ResultsIncidence of EBV‐pos DLBCL was 6.9% with 5‐year survival of 65% vs 82% in EBV‐neg DLBCL (P = 0.018). EBV‐pos tissues had similar expression of T‐cell genes compared to EBV‐neg DLBCL but higher levels of the antigen‐presenting molecule B2M. This was countered by elevated PD‐L1, PD‐L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 “M2” macrophage score.ConclusionIn EBV‐pos DLBCL, the TME is immuno‐tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.

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Section: Introductionmentioning

confidence: 99%

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Keane

Tobin

Gunawardana

et al. 2019

European J of Haematology

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“…[2] Evidence suggests that the immunosuppressive environment surrounding cancer cells contributes to the poor efficacy of therapeutic antibodies and chemotherapy. [3] We hypothesized that natural killer (NK) cells in patients with refractory NHL exhibit poor function with impaired capacity to mediate direct cytotoxic and antibody-mediated killing. [4, 5] NK cells are innate effectors, residing in lymphoid tissues, spleen and peripheral blood at low frequency (5–10% of lymphocytes).…”

Section: Introductionmentioning

confidence: 99%

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Bachanová

Sarhan

DeFor

et al. 2017

Cancer Immunol Immunother

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We report a novel phase 2 clinical trial in patients with poor prognosis refractory NHL testing the efficacy of haploidentical donor NK cell therapy (NK dose 0.5–3.27 × 107 NK cells/kg) with rituximab and IL-2.(clinicaltrials.gov NCT01181258) Therapy was tolerated without graft-versus-host-disease, cytokine release syndrome, or neurotoxicity. Of 15 evaluable patients, 4 had objective responses (26.6%) at 2 months: 2 had complete response lasting 3 and 9 months. Circulating donor NK cells persisted for at least 7 days after infusion at the level between 0.6–16 cells/µl. Responding patients had lower levels of circulating host derived Tregs (17±4 vs. 307±152 cells/µL; p=0.008) and myeloid derived suppressor cells (MDSC) at baseline (6.6%±1.4% vs. 13.0%±2.7%; p=0.06) than non-responding patients. Lower circulating Tregs correlated with low serum levels of IL-10 (R2=0.64; p<0.003; n=11), suggestive of an immunosuppressive milieu. Low expression of PD-1 on recipients T cells before therapy was associated with response. Endogenous IL-15 levels were higher in responders than non-responding patients at the day of NK cell infusion (mean±SEM: 30.0±4.0; n=4 vs 19.0±4.0 pg/ml; n=8; p=0.02) and correlated with NK cytotoxicity at day 14 as measured by expression of CD107a (R2=0.74; p=0.0009; n=12). In summary, our observations support development of donor NK cellular therapies for advanced NHL as a strategy to overcome chemoresistance. Therapeutic efficacy may be further improved through disruption of the immunosupressive environment and infusion of exogenous IL-15.

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“…For example, in cHL, FOXP3 expression by immunohistochemistry in biopsy specimens is correlated with improved overall survival [121, 122]. Although the underlying mechanisms are unclear, it is possible that Treg cells may directly inhibit the proliferation of HRS cells [123]. Alternatively, as has been shown in solid tumors [124], the increased frequency of Tregs in the tumor environment may occur in response to the activation of an anti-tumor immune response.…”

Section: Recruitment and Expansion Of Immunosuppressive Cellsmentioning

confidence: 99%

Mechanisms of Immune Tolerance in Leukemia and Lymphoma

Curran

Godfrey

Kline

2017

Trends in Immunology

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The mechanisms through which immune responses are generated against solid cancers are well-characterized, and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways which regulate immune activation or tolerance are less clear. Growing evidence suggests that, while a number of immune escape pathways are shared between hematological and solid malignancies, there are several unique pathways exploited by leukemia and lymphoma. Below, we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapy approaches.

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Role of the tumor microenvironment in mature B-cell lymphoid malignancies

Cited by 81 publications

References 147 publications

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Mechanisms of Immune Tolerance in Leukemia and Lymphoma

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