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Journal of Peking University (Health Sciences) ›› 2024, Vol. 56 ›› Issue (3): 512-518. doi: 10.19723/j.issn.1671-167X.2024.03.019

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

Xiaodong CHAI1,2,Ziwen SUN1,Haishuang LI1,Liangyi ZHU1,Xiaodan LIU1,2,Yantao LIU1,Fei PEI1,2,*(),Qing CHANG3,*()   

  1. 1. Department of Pathology, Peking University Third Hospital, Beijing 100191, China
    2. Department of Pathology, Peking University School of Basic Medical Sciences, Beijing 100191, China
    3. Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Beijing 100070, China
  • Received:2022-10-18 Online:2024-06-18 Published:2024-06-12
  • Contact: Fei PEI,Qing CHANG E-mail:peifei@bjmu.edu.cn;changqing055@bjni.org.cn
  • Supported by:
    the National Natural Science Foundation of China(81972353);the National Natural Science Foundation of China(81101900)

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Abstract:

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.

Key words: Medulloblastoma, Tumor microenvironment, CD8-positive T-lymphocytes, Chemokine CXCL11

CLC Number: 

  • R739.41

Figure 1

The characteristics of CD8+ T cells infiltration in MB subtypes * P<0.05, ** P<0.01, **** P<0.000 1. A, heat map representing of cell type enrichment scores in 48 MB patients (n=12 per subtype); B, the characteristic index of CD8+T cells in WNT subtype of MB is higher; C, the characteristic index of exhausted CD8 T cells in WNT and SHH subtype of MB is lower; D, the characteristic index of cytotoxic T cells in four subtypes of MB has no significant difference; E, representative IHC images for CD8+ T cells in primary MB specimens (IHC ×20); F, WNT subtype of MB has the most infiltration of CD8+ T cells, with average of 10 fields of view for each tumor. MB, medulloblastoma; WNT, wingless subtype; SHH, sonic hedgehog subtype; DC, dendritic cell; IHC, immunohistochemistry."

Figure 2

The expression of CD8A in MB subtypes in GEO and its relation to prognosis of the patients *** P<0.001, **** P<0.000 1. A, the CD8A mRNA expression of WNT subtype of MB is significantly higher than the other three subtypes; B, the high CD8A mRNA expression is associated with the longer survival (P=0.036). MB, medulloblastoma; WNT, wingless subtype; SHH, sonic hedgehog subtype; GEO, Gene Expression Omnibus."

Figure 3

The differential expression of chemokine CXCL11 and its receptor CXCR3 in MB subtypes ** P<0.01, **** P<0.000 1. A, screening of chemokines in NanoString PanCancer IO360TM data and GEO database; B, the CXCL11 mRNA expression of WNT subtype of MB in NanoString PanCancer IO360TM data is higher (P=0.009 6); C, the CXCL11 mRNA expression of WNT subtype of MB in GEO database is significantly higher than the other three subtypes; D, the more infiltration of CD8+ T cells is positively correlated with the higher expression of CXCL11 (r=0.491 8, P=0.000 4); E, representative IF images for CD8 positive cells and CXCR3 positive cells in primary MB specimens (IF ×20, n=12). IF, immunofluorescence; MB, medulloblastoma; WNT, wingless subtype; SHH, sonic hedgehog subtype; GEO, Gene Expression Omnibus."

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