| Sumario: | Simple Summary: Human leukocyte antigen class I (HLA-I) molecules can modulate anti-tumour immune responses from CD8+ T cells and NK cells. However, how deregulated HLA-I expression impacts clinical outcomes in cancer patients has remained unclear. Using computational approaches, we investigated the association of HLA-I molecules with patient survival by analysing gene expression datasets across multiple cancers. We observed a trend toward poor survival in patients with high HLA-I expression in lower-grade gliomas. Moreover, the favourable prognostic association of CD56dim NK cells was attenuated in the context of abundant HLA-I, as suggested by the correlation between NK cell receptors NKG2A/C/E and HLA-E. Overall, our study provides a computational framework that offers insights into HLA-I-mediated modulation of cytotoxic NK cell activity using cancer gene expression datasets, with potential applicability for other diseases. Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56dim and CD56bright NK cells. Results: Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56dim NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56dim NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of HLA-E and NKG2A predicted poor survival outcomes in LGG patients, whereas low HLA-E and high NKG2C/E abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56dim NK cell subset. Conclusions: Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56dim NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms.
|
|---|