Pediatric brain tumor patients display altered immune activation and reduced lymphopoiesis at the onset of disease

Abstract

Optimal immune function is crucial in preventing cancer development and growth and for the success of anti-cancer therapies. Here, we characterized the peripheral immunological status of 83 steroids-naïve pediatric patients with central nervous system neoplasia at the disease onset. Tumors were classified into low-grade gliomas (LGG), high-grade gliomas (HGG), medulloblastoma, and other tumors. We revealed that glioma patients showed an altered lymphocyte pool. T-cells of HGG patients shifted from naïve to effector memory phenotype. LGG patients exhibited T-cell central memory expansion and higher T-cell activation. Interestingly, HGG patients displayed reduced thymic function. Furthermore, LGG and HGG patients showed reduced activated B-cells and suboptimal B-cell formation. Our data demonstrate that glioma patients have reduced lymphopoiesis at the disease onset, which could contribute to the systemic lymphopenia characterizing these patients. This study offers novel insights into the immunological status of brain tumor patients which may help in designing more effective treatments.

Fig. 1. T-cell phenotypic landscape of healthy donors (HD), HGG and LGG tumor patients.

White blood cell count (A), lymphocyte count and frequency (B) in peripheral blood of patients and HD. C Uniform manifold approximation and projection (UMAP) embedding of CD4⁺ T-cells derived from PBMC samples of HD, HGG and LGG tumor patients. Right plot illustrates the UMAP of merged HD,and HGG and LGG groups of CD4⁺ T-cells defined using phenotypic and functional T-cell markers. D Frequency of Central Memory, CM, E Effector Memory, EM, F naïve and G recent thymic emigrants CD4⁺ T-cells. H UMAP embedding of CD8⁺ T-cells derived from PBMC samples of HD, and HGG and LGG tumor patients. Right plot illustrates the UMAP of merged HD, HGG and LGG groups of CD8⁺ T-cells defined using phenotypic and functional T-cell markers. I CM, J EM, and K naïve CD8⁺ T-cells frequencies. For UMAP analysis each plot is representative of 8 concatenated samples per group and were generated using phenotypic and functional markers defined in Supplementary Table 2. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 2. Assesment of peripheral T-cell activation in HGG and LGG tumor patients and healthy controls.

CD69, HLA-DR and CD38 positive cells in CD4⁺ Central Memory, CM (A), and Effector Memory, EM (B), and CD8⁺ CM (C) and EM (D) T-cells in HD (blue), LGG (green) and HGG (red) tumor patients. *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 3. B- and NK-cell phenotypic evsluation in HGG and LGG tumor patients and healthy controls.

A Activated, B Naïve, C Transitional, D Memory B-cell frequencies in HD (blue), LGG (green) and HGG (red) tumor patients. E Plasmablasts and F atypical B-cell frequencies. G CD56^bright, J CD56^dim and K CD56^dimCD57⁺ NK-cell count and frequencies in HD (blue), LGG (green), and HGG (red) tumor patients. *p < 0.05.

Fig. 4. T- and B-cell neogenesis is impaired in brain tumor patients.

A βTREC, and B sjTREC quantification per 150,000 cells in HD (blue), LGG (green) and HGG (red) tumor patients. C cjKREC and (D) sjKREC quantification per 150,000 cells in HD (blue), LGG (green) and HGG (red) tumor patients. *p < 0.05, **p < 0.01, ***p < 0.001.