Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis

Liang, Kung–Hao; Chang, Che-Chang; Wu, Kuo-Sheng; Yu, Alice L.; Sung, Shian-Ying; Lee, Yi-Yen; Liang, Mindy; Chen, Hsin‐Hung; Fen, Jun-Jeng; Chao, Meng-En; Liao, Yi-Ting; Wong, Tai-Tong

doi:10.1038/s41598-021-02651-y

Cited by 8 publications

(6 citation statements)

References 45 publications

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“…We found 10 genes with DMPs that were conserved across subgroups suggesting a shared genetic background by subgroup may underlie some of the observed sexual dimorphism in medulloblastoma. Pathways identified within subgroups were largely signaling pathways including TGF-b, neurotrophic receptors, and NOTCH, which are known to impact prognosis in medulloblastoma and according to our findings may vary by sex within subgroups (34,47,48). Importantly, we identified four genes that housed sex-DMPs that also have chemotherapies available that could be studied in a sex-specific manner to improve outcomes for males and females with medulloblastoma.…”

Section: Discussionmentioning

confidence: 57%

Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors

et al. 2023

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BackgroundMedulloblastoma, the most common malignant pediatric brain tumor, displays marked sex differences in prevalence of the four main molecular subgroups: SHH, WNT, Group 3 and Group 4. Males are more frequently diagnosed with SHH, Group 3 and 4 tumors, which have worse prognoses than WNT tumors. Little is known about sex differences in methylation profiles within subgroups.MethodsUsing publicly available methylation data (Illumina HumanMethylation450K array), we compared beta values for males versus females. Differentially methylated positions (DMP) by sex within medulloblastoma subgroups were identified on the autosomes. DMPs were mapped to genes and Reactome pathway analysis was run by subgroup. Kaplan-Meier survival curves (Log-Rank p-values) were assessed for each sex within subgroup. MethylCIBERSORT was used to investigate the tumor microenvironment using deconvolution to estimate the abundances of immune cell types using DNA methylation data.ResultsThere were statistically significant differences in sex by medulloblastoma subgroups (chi-squared p-value=0.00004): Group 3 (n=144; 65% male), Group 4 (n=326; 67% male), SHH (n=223; 57% male) and WNT (n=70; 41% male). Females had worse survival than males for SHH (p-value=0.02). DMPs by sex were identified within subgroups: SHH (n=131), Group 4 (n=29), Group 3 (n=19), and WNT (n=16) and validated in an independent dataset. Unsupervised hierarchical clustering showed that sex-DMPs in SHH did not correlate with other tumor attributes. Ten genes with sex DMPs (RFTN1, C1orf103, FKBP1B, COL25A1, NPDC1, B3GNT1, FOXN3, RNASEH2C, TLE1, and PHF17) were shared across subgroups. Significant pathways (p<0.05) associated with DMPs were identified for SHH (n=22) and Group 4 (n=4) and included signaling pathways for RET proto-oncogene, advanced glycosylation end product receptor, regulation of KIT, neurotrophic receptors, NOTCH, and TGF-β. In SHH, we identified DMPs in four genes (CDK6, COL25A1, MMP16, PRIM2) that encode proteins which are the target of therapies in clinical trials for other cancers. There were few sex differences in immune cell composition within tumor subgroups.ConclusionThere are sexually dimorphic methylation profiles for SHH medulloblastoma where survival differences were observed. Sex-specific therapies in medulloblastoma may impact outcomes.

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Section: Discussionmentioning

confidence: 57%

Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors

et al. 2023

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“…NK cells can migrate to TME and exhibit cytolytic activity to kill tumor cells directly without specific immunization. NK cells were found to exist in MBs in the previous studies [ 44 , 52 , 53 , 54 ]. It was reported that NK cells can suppress SHH MB tumor growth in a Daoy xenografted mouse model [ 53 ].…”

Section: Discussionmentioning

confidence: 93%

Clinical and Molecular Features in Medulloblastomas Subtypes in Children in a Cohort in Taiwan

Sung

Huang

et al. 2022

Cancers

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Medulloblastoma (MB) was classified into four molecular subgroups: WNT, SHH, group 3, and group 4. In 2017, 12 subtypes within 4 subgroups and 8 subtypes within non-WNT/non-SHH subgroups according to the differences of clinical features and biology were announced. In this study, we aimed to identify the heterogeneity of molecular features for discovering subtype specific factors linked to diagnosis and prognosis. We retrieved 70 MBs in children to perform RNA sequencing and a DNA methylation array in Taiwan. Integrated with clinical annotations, we achieved classification of 12 subtypes of pediatric MBs in our cohort series with reference to the other reported series. We analyzed the correlation of cell type enrichment in SHH MBs and found that M2 macrophages were enriched in SHH β, which related to good outcomes of SHH MBs. The high infiltration of M2 macrophages may be an indicator of a favorable prognosis and therapeutic target for SHH MBs. Furthermore, C11orf95-RELA fusion was observed to be associated with recurrence and a poor prognosis. These results will contribute to the establishment of a molecular diagnosis linked to prognostic indicators of relevance and help to promote molecular-based risk stratified treatment for MBs in children.

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“…This is often dependent on the cytokines secreted by the other immune cells into TME and also the tumor by itself which negatively contributes to NK cell activation status secreting for example TGFβ or IL-10. This favors a resting phenotype, frequently found in tumor tissues in association with poor prognosis [ 121 , 122 ].…”

Section: Natural Killer (Nk) Cells: Overviewmentioning

confidence: 99%

Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies

Giansanti,

Theinert,

Boeing

et al. 2023

Mol Cancer

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Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.

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Notch signaling and natural killer cell infiltration in tumor tissues underlie medulloblastoma prognosis

Cited by 8 publications

References 45 publications

Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors

Sex differences in methylation profiles are apparent in medulloblastoma, particularly among SHH tumors

Clinical and Molecular Features in Medulloblastomas Subtypes in Children in a Cohort in Taiwan

Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies

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