Immunological Analysis of Brain Cancer

Division Of Basic Sciences - Nci

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Abstract

Aim 1: The existence of NKT cells in glioblastoma has been controversial as studies with a small number of clinical samples reported conflicting results. To examine the prevalence of NKT cells, we sought the transcripts of NKT cells by using The Cancer Gene Atlas glioblastoma data set with 168 patient samples. We found that a fraction of patients contains NKT cell transcripts. Those patients had significantly higher expression levels of cytokines and chemokines that are known to facilitate tumor immunity. However, the observation was not translated into a prolonged survival of patients. Aim 2: The lipid profiling of human glioblastoma (high-grade glioma) cell lines, human low-grade glioma cell lines, and normal human astrocytes was conducted. We found that glioblastoma had a significantly different profile from low-grade glioma and normal astrocytes. The lipid greatly enriched in glioblastoma can potentially be recognized by human NKT cells. Aim 3: The existence and functions of MAIT cells in glioblastoma are less understood than NKT cells. We took a similar approach, which we took to studying NKT cells under Aim1, to examine the prevalence of MAIT cells in glioblastoma patient samples. We found that 8.3% out of 164 patients had MAIT cells in their tumors. MAIT-positive patients had significantly upregulated MR1. Since the number of MAIT-positive patients was small, we could not assess the impact of MAIT cell infiltration into tumors on patient survival. However, the MR1 expression level, which was higher in MAIT-positive patients, had a significant negative correlation with patient survival. MAIT-positive patients had significantly upregulated genes contained in the Negative Regulation of Immune Response. Multiple neutrophil migration/activation pathways were found to be significantly upregulated in MAIT-positive patients by the Gene Set Enrichment Analysis using a Gene Ontogeny Biological Pathway. Neutrophil degranulation-related genes and myeloid-derived suppressor cells (MDSCs) signature genes were also significantly upregulated in MAIT-positive patients, suggesting that MAIT-positive patients have activated tumor-associated neutrophils (TANs) and MDSCs. Multiple TAN/MDSC-associated immunoregulatory genes were upregulated in MAIT-positive patients, suggesting a MAIT/MR1-TAN/MDSC immunoregulatory pathway. The activity of the pathway was suggested in four additional cancer types. These data indicate that MAIT cells contribute to myeloid cell-mediated immune suppression in GBM.