The therapeutic potential of natural killer cells to target medulloblastoma

Pérez‐Martínez, Antonio; Fernández, Lucía; Díaz, Miguel Ángel

doi:10.1080/14737140.2016.1184978

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…In order to engage NK cells to kill medulloblastoma cells, expression of ligand for the activation receptors might be required. 47 Expression of ligands for NKG2D (NK cell activation receptor) are elevated in 50% of medulloblastomas. 48 In line with this, several patients have been intrathecally treated with LAK cells, showing a remission of the medulloblastoma.…”

Section: Discussionmentioning

confidence: 99%

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

et al. 2017

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Pediatric medulloblastomas are the most frequently diagnosed embryonal tumors of the central nervous system. Current therapies cause severe neurological and cognitive side effects including secondary malignancies. Cellular immunotherapy might be key to improve survival and to avoid morbidity. Efficient killing of tumor cells using immunotherapy requires to overcome cancer-associated strategies to evade cytotoxic immune responses. Here, we examined the immune response and immune evasion strategies in pediatric medulloblastomas. Cytotoxic T-cells, infiltrating medulloblastomas with variable activation status, showed no correlation with overall survival of the patients. We found limited numbers of PD1+ T-cells and complete absence of PD-L1 on medulloblastomas. Medulloblastomas downregulated immune recognition molecules MHC-I and CD1 d. Intriguingly, expression of granzyme inhibitors SERPINB1 and SERPINB4 was acquired in 23% and 50% of the tumors, respectively. Concluding, pediatric medulloblastomas exploit multiple immune evasion strategies to overcome immune surveillance. Absence of PD-L1 expression in medulloblastoma suggest limited or no added value for immunotherapy with PD1/PD-L1 blockers.

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Section: Discussionmentioning

confidence: 99%

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

et al. 2017

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“…Using multicolor FACS analysis in a cohort of 6 medulloblastomas, it was shown that medulloblastoma exhibited a different immune microenvironment compared to 3 other pediatric brain tumor entities and the findings were validated by gene expression. 16 Natural killer cell (NK cell) therapy was among the first immunotherapeutic approaches that have been proposed for medulloblastoma (see 17 for review). Further, Margol et al 18 showed that tumor-associated macrophages were more numerous in SHH medulloblastoma than in Group 3 and Group 4 tumors and proposed macrophages as therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Subgroup-specific immune and stromal microenvironment in medulloblastoma

et al. 2018

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Knowledge on immune and stromal cells in medulloblastoma microenvironment is still limited as previous work was frequently restricted by low sample size and the lack of molecular subgroup information. We characterized 10 microenvironment cell populations as well as from gene expression in 1422 brain tumors and 763 medulloblastomas. All in all, medulloblastomas showed low expression of immune markers. Still, there were substantial differences with a clustering of medulloblastoma subgroups according to their microenvironment profile. Specifically, SHH medulloblastomas displayed strong signatures of fibroblasts, T cells and macrophages, while markers of cytotoxic lymphocytes were enriched in Group 4 tumors. gene expression appeared to be relatively high in single SHH and WNT cases but was undetectable by immunohistochemistry. In addition, two diverse immuno-stromal patterns were identified, indicating distinct types of local tumor immunosuppression, which were primarily controlled by either macrophage and regulatory T cell-mediated mechanisms or immunosuppressive cytokines and checkpoints, respectively. None of the immune cell signatures had an independent prognostic value in the present dataset after multiple testing correction. These results suggest a mild, but subgroup-specific infiltration of immune cells in medulloblastoma.

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“…Natural killer (NK) cells play a major role in the immune defense against malignant disease by recognizing a broad spectrum of tumor cells without specific antigen identification [120]. NK cells are controlled by both activating and inhibitory receptors, and MB cell lines express specific ligands that are able to trigger NK activation, enabling the lysis of MB cell lines in vitro regardless of the presence or absence of the stem cell marker CD133 [121].…”

Section: Natural Killer Cellsmentioning

confidence: 99%

Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches

Menyhárt

Győrffy

2020

Cancer Metastasis Rev

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Medulloblastoma (MB) is the most common malignant childhood tumor of the brain. Multimodal treatment consisting of surgery, radiation therapy, and chemotherapy reduced cumulative incidence of late mortality but increased the incidence of subsequent neoplasms and severe, incapacitating chronic health conditions. Present treatment strategies fail to recognize heterogeneity within patients despite wide divergence in individual responses. The persistent mortality rates and serious side effects of non-targeted cytotoxic therapies indicate a need for more refined therapeutic approaches. Advanced genomic research has led to the accumulation of an enormous amount of genetic information and resulted in a consensus distinguishing four molecular subgroups, WNTactivated, SHH-activated, and Group 3 and 4 medulloblastomas. These have distinct origin, demographics, molecular alterations, and clinical outcomes. Although subgroup affiliation does not predict response to therapy, new subgroup-specific markers of prognosis can enable a more layered risk stratification with additional subtypes within each primary subgroup. Here, we summarize subgroup-specific genetic alterations and their utility in current treatment strategies. The transition toward molecularly targeted interventions for newly diagnosed MBs remains slow, and prospective trials are needed to confirm stratifications based on molecular alterations. At the same time, numerous studies focus at fine-tuning the intensity of invasive radio-and chemotherapies to reduce intervention-related long-term morbidity. There are an increasing number of immunotherapy-based treatment strategies including immune checkpoint-inhibitors, oncolytic viruses, CART therapy, and NK cells in recurrent and refractory MBs. Although most trials are in early phase, there is hope for therapeutic breakthroughs for advanced MBs within the next decade.

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The therapeutic potential of natural killer cells to target medulloblastoma

Cited by 15 publications

References 34 publications

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

Subgroup-specific immune and stromal microenvironment in medulloblastoma

Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches

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