A novel role of HLA class I in the pathology of medulloblastoma

Smith, Courtney; Santi, Mariarita; Rajan, Bhargavi; Choi, Mi Rim; Rood, Brian R.; Cornelison, Robert; MacDonald, Tobey J.; Vukmanović, Stanislav

doi:10.1186/1479-5876-7-59

Cited by 20 publications

(30 citation statements)

References 52 publications

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“…Thus, we find that increased MHC class I APM is associated with reduced survival of GBM patients. A similar trend was observed in medulloblastoma where increased MHC class I APM was associated with unfavorable prognostic marker expression (Smith et al, 2009). We then asked whether higher MHC class I APM expression in patient tumors had any impact on tumor lymphocyte infiltration as measured by pathological assessment (Rutledge et al, 2013).…”

Section: Resultssupporting

confidence: 69%

Causal Mechanistic Regulatory Network for Glioblastoma Deciphered Using Systems Genetics Network Analysis

et al. 2016

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Summary We developed the transcription factor (TF)-target gene database and the SYstems Genetics Network AnaLysis (SYGNAL) pipeline to decipher transcriptional regulatory networks from multi-omic and clinical patient data, and applied these tools to 422 patients with glioblastoma multiforme (GBM). The resulting gbmSYGNAL network predicted 112 somatically mutated genes or pathways that act through 74 TFs and 37 miRNAs (67 not previously associated with GBM) to dysregulate 237 distinct co-regulated gene modules associated with patient survival or oncogenic processes. The regulatory predictions were associated to cancer phenotypes using CRISPR-Cas9 and small-RNA perturbation studies, and also demonstrated GBM specificity. Two pairwise combinations (ETV6–NFKB1 and romidepsin–miR-486-3p) predicted by the gbmSYGNAL network had synergistic anti-proliferative effects. Finally, the network revealed that mutations in NF1 and PIK3CA modulate IRF1-mediated regulation of MHC class I antigen processing and presentation genes to increase tumor lymphocyte infiltration and worsen prognosis. Importantly, SYGNAL is widely applicable for integrating genomic and transcriptomic measurements from other human cohorts.

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Section: Resultssupporting

confidence: 69%

Causal Mechanistic Regulatory Network for Glioblastoma Deciphered Using Systems Genetics Network Analysis

et al. 2016

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“…Following IRB approval for the construction and analysis of tissue microarrays and normal cerebellar tissue specimens, medulloblastoma and adult glioblastoma tissue microarrays were constructed as previously described [7, 15]. Deidentified cerebellum tissue was obtained post mortem from six patients from Children's National Medical Center, age ranging from prenatal 28 weeks to postnatal 3 years.…”

Section: Methodsmentioning

confidence: 99%

“…This may have important consequences, as demonstrated by negative prognostic impact of HLA class I expression in several types of cancer [4–7]. This function contrasts with the implied role of HLA class I molecules in enabling tumor destruction by the immune system, where expression of HLA class I is a favorable prognostic sign [8–11].…”

Section: Introductionmentioning

confidence: 99%

“…Here, low levels of HLA class I were associated with poor outcome, whereas complete loss of expression was associated with extended survival. Our recent studies on medulloblastoma provided an insight into the mechanism of the contribution of HLA class I to the poor prognosis of the disease [7]. These studies showed that HLA class I was expressed in a subset of medulloblastomas with poor prognosis, and that interaction of two subunits of MHC class I induced ERK1/2 phosphorylation and increased the migratory potential of medulloblastoma cells [7].…”

Section: Introductionmentioning

confidence: 99%

“…Our recent studies on medulloblastoma provided an insight into the mechanism of the contribution of HLA class I to the poor prognosis of the disease [7]. These studies showed that HLA class I was expressed in a subset of medulloblastomas with poor prognosis, and that interaction of two subunits of MHC class I induced ERK1/2 phosphorylation and increased the migratory potential of medulloblastoma cells [7]. We here extend these findings to formally show that fully assembled HLA class I molecules are not required for the signaling function and that heterogeneity of HLA class I expression reflects the dynamic developmental pattern of HLA expression by neurons of the external granular layer in cerebellum, the presumed precursor cell of most medulloblastomas.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of signaling function and expression of HLA class I molecules in medulloblastoma

et al. 2010

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Although known for the important function in the immune system, MHC class I molecules are increasingly ascribed an alternative role in modifying signal transduction. In medulloblastoma, HLA class I molecules are associated with poor prognosis, and can induce ERK1/2 activation upon engagement with ligands that bind to incompletely assembled complexes (so called open conformers). We here demonstrate that ERK1/2 activation in medulloblastoma can occur in the absence of endogenously synthesized β2m, formally excluding involvement of closed HLA class conformation. In addition, several experimental observations suggest that heterogeneity of HLA class I expression may be a reflection of the status of original cells before transformation, rather than a consequence of immune-based selection of HLA-loss mutants. These results contribute to our understanding of an immune system-independent role of HLA class I in the pathology of medulloblastoma, and cancer in general.

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Going back to class I: MHC and immunotherapies for childhood cancer

Haworth

Leddon

Chen

et al. 2014

Pediatr Blood Cancer

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After decades of unfulfilled promise, immunotherapies for cancer have finally reached a tipping point, with several FDA approved products now on the market and many more showing promise in both adult and pediatric clinical trials. Tumor cell expression of MHC Class I has emerged as a potential determinant of the therapeutic success of many immunotherapy approaches. Here we review current knowledge regarding MHC Class I expression in pediatric cancers including a discussion of prognostic significance, the opposing influence of MHC on T-cell versus NK-mediated therapies, and strategies to reverse or circumvent MHC down-regulation.

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A novel role of HLA class I in the pathology of medulloblastoma

Cited by 20 publications

References 52 publications

Causal Mechanistic Regulatory Network for Glioblastoma Deciphered Using Systems Genetics Network Analysis

Causal Mechanistic Regulatory Network for Glioblastoma Deciphered Using Systems Genetics Network Analysis

Characterization of signaling function and expression of HLA class I molecules in medulloblastoma

Going back to class I: MHC and immunotherapies for childhood cancer

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