Abstract
The binding of platelet-derived growth factor D (PDGF-DD) to the NKp44 receptor activates a distinct transcriptional program in primary IL-2 expanded human natural killer (NK) cells. We were interested in knowing if the PDGF-DD-NKp44 pathway of NK cell activation might play a clinically relevant role in anti-tumor immunity. In order to address this question, we determined transcriptional signatures unique to resting, IL-2 expanded, and PDGF-DD activated, NK cells, in addition to different T cell subsets, and established the abundance of these immune cell phenotypes in The Cancer Genome Atlas (TCGA) low-grade glioma (LGG) dataset using CIBERSORT. Our results show that LGG patient tumors enriched for either the PDGF-DD activated NK cell or memory CD8+ T cell phenotypes are associated with a more favorable prognosis. Combined cell phenotype analyses revealed that patients with LGG tumors enriched for the PDGF-DD activated NK cell phenotype and the CD4+ T helper cell phenotype had a more favorable prognosis. High expression of transcripts encoding members of the killer cell lectin-like receptor (KLR) family, such as KLRK1 and KLRC2, KLRC3 and KLRC4 in LGG tumors were associated with more favorable prognosis, suggesting that these NK cell family receptors may play a prominent role in LGG anti-tumor immunity. Finally, many of the TCGA findings were reciprocated in LGG patients from the Chinese Glioma Genome Atlas (CGGA) dataset. Our results provide transcriptomic evidence that PDGF-DD activated NK cells and KLR family receptors may play an important clinical role in immune surveillance of LGG.
Highlights
Diffuse and infiltrative low-grade gliomas (LGGs) are derived from the malignant transformation of astrocytes or oligodendrocytes [1]
LGG tumors enriched for the memory CD8+ T cell phenotype were associated with improved prognosis (Figure 5B). These results show that LGG tumors enriched for the memory CD8+ T cell phenotype mitigate the pro-tumorigenic effects of PDGFD because they are associated with improved prognosis
We found that enrichment of the signature of PDGF-DD activated NK cells (SPANK) phenotype in LGG tumors was associated with improved prognosis in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets
Summary
Diffuse and infiltrative low-grade gliomas (LGGs) are derived from the malignant transformation of astrocytes or oligodendrocytes [1]. Whilst grade I LGGs are readily resectable benign tumors, grade II LGG display pathologic traits and inexorably progress to high grade gliomas, such as glioblastoma (GBM), with terminal neurological decline [1, 2]. Despite growing understanding of LGG pathogenesis, clinical outcomes have failed to improve for young adults [6]. There is an urgent need to understand effective anti-tumor immunity in LGG. Whilst the phenotype and function of tumor-infiltrating lymphocytes (TILs) have been explored for high grade gliomas [8], the prognostic value of TIL subsets and the molecular pathways of tumor recognition for LGG remain unclear
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