[Clinicopathological characteristics of the CD8+ T lymphocytes infiltration and its mechanism in distinct molecular subtype of medulloblastoma].

OBJECTIVE: To investigate the characteristics of the CD8+ T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8+ T cells infiltration and prognosis, to study the function of C-X-C motif chemokine ligand 11 (CXCL11) and its receptor in CD8+ T cells infiltration into tumors and to explore the potential mechanism, and to provide the necessary clinicopathological basis for exploring the immunotherapy of MB. METHODS: In the study, 48 clinical MB samples (12 cases in each of 4 subtypes) were selected from the multiple medical center from 2012 to 2019. The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString PanCancer IO360TM Panel (NanoString Technologies). Immunohistochemistry (IHC) staining of formalin-fixed, paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8+ T cells in the MB four subtypes. Through bioinformatics analysis, the relationship between CD8+T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated. The expression of CXCR3 receptor on the surface of CD8+T cells in MB was verified by double immunofluorescence staining, and the underlying molecular mechanism of CD8+T cells infiltration into the tumor was explored. RESULTS: The characteristic index of CD8+T cells in the WNT subtype of MB was relatively high, suggesting that the number of CD8+T cells in the WNT subtype was significantly higher than that in the other three subtypes, which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus (GEO) database analysis by using R2 online data analysis platform. And the increase of CD8+T cells infiltration was positively correlated with the patient survival. The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes. Immunofluorescence staining showed the presence of CXCL11 receptor, CXCR3, on the surface of CD8+T cells, suggesting that the CD8+T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3. CONCLUSION: The CD8+T cells infiltrate more in the WNT subtype MB than other subtypes. The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system, and the patients with more infiltration of CD8+T cells in tumor have better prognosis. This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8+T cells infiltration in MB, and give a new potential therapeutic target for the future immunotherapy of MB.

PKM2 aggregation drives metabolism reprograming during aging process.

While protein aggregation's association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.