Single-cell transcriptomics reveals regulators underlying immune cell diversity and immune subtypes associated with prognosis in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A+ dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell–cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A+ DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.

The Role of NK Cells in EBV Infection and EBV-Associated NPC

“…It is important to note that NK cells do not interact solely with NPC cells. NK cells in NPC have been reported to interact with macrophages [126,127], dendritic cells [127] and dysfunctional CD8 T cells [127]. NK-tumor interactions included HLA-C/KIR2DL4, HLA-E/CD94 (KLD1), TIM3 (HAVCR2)/Galectin-9, CD96-PVR/Nectin1 and TIGIT-PVR/Nec-tin2 [126,127].…”

“…NK cells in NPC have been reported to interact with macrophages [126,127], dendritic cells [127] and dysfunctional CD8 T cells [127]. NK-tumor interactions included HLA-C/KIR2DL4, HLA-E/CD94 (KLD1), TIM3 (HAVCR2)/Galectin-9, CD96-PVR/Nectin1 and TIGIT-PVR/Nec-tin2 [126,127]. HLA-E/CD94 interaction is of notable interest, since HLA-E is a ligand of NKG2A, which is a receptor expressed by NK cells that is involved in EBV restriction [65,76,79].…”

“…HLA-E/CD94 interaction is of notable interest, since HLA-E is a ligand of NKG2A, which is a receptor expressed by NK cells that is involved in EBV restriction [65,76,79]. Additionally, TIM3-Galectin-9 and TIGIT-Nectin2 interactions were also noted between NK cells and dysfunctional CD8 cells, macrophages and dendritic cells, respectively [126,127].…”

“…[160] HAVCR2 (TIM3) of NK interacts with Galectin-9 on tumor cells, dysfunctional CD8 cells, macrophages and dendritic cells in NPC. [126,127] CD96 TIGIT PVR/Nectin1 PVR/Nectin2…”

Nasopharyngeal carcinoma joins the single‐cell party

“…A new study by Chen et al. [7] has applied this scRNA‐seq approach to nasopharyngeal carcinoma (NPC). NPC is a relatively uncommon cancer type that is found mainly in East and Southeast Asia and is strongly associated with Epstein‐Barr virus (EBV) infection.…”