Exploratory associations of KIR2DS4/HLA-A immunogenetic profiles with nasopharyngeal carcinoma susceptibility and pretreatment plasma EBV DNA phenotypes

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection and host immune genetic background. Killer-cell immunoglobulin-like receptors (KIRs) and HLA class I molecules regulate antiviral and antitumor immune surveillance, but their relationship with pretreatment plasma EBV DNA levels in NPC remains unclear. We conducted a single-center case-control study including 204 patients with histopathologically confirmed NPC and 201 healthy controls from southern China. KIR gene content, gene-content-defined KIR haplotype-combination categories, KIR2DS4 subtypes, HLA-A alleles, and selected KIR/HLA-A profiles were analyzed. Among NPC patients, 182 with available pretreatment plasma EBV DNA records were included in an exploratory case-only phenotype analysis. Pretreatment EBV DNA was analyzed as a continuous variable after log₁₀ transformation. Exploratory flow-cytometric analyses were performed in tissue-source-specific subsets. Compared with healthy controls, NPC patients showed higher detection frequencies of KIR2DS4 and KIR3DL1 and a lower frequency of the BB gene-content-defined KIR haplotype-combination category. Among KIR2DS4-positive individuals, the KIR2DS4 Deleted/Deleted subtype was nominally enriched in NPC patients. HLA-A*11:01 was less frequent, whereas HLA-A*02:07 was more frequent, in NPC patients than in controls. Among 182 NPC patients with pretreatment EBV DNA records, the HLA-A*11:01-negative/KIR2DS4 Deleted/Deleted profile was associated with significantly higher log₁₀-transformed pretreatment EBV DNA levels (median 3.94 vs. 2.81; P = 0.0037). This association persisted after adjustment for age, sex, clinical stage, and TNM-related variables (β = 1.36, P = 0.013). Longitudinal EBV DNA kinetic variables showed no stable association with KIR/HLA-A profiles. Flow-cytometric analyses showed a positive sample-level correlation between peripheral-blood KIR2DS4-positive and NKG2D-positive lymphocyte-related signals, whereas tumor CTL NKG2D positivity showed a nominal difference by EBV DNA level but was not robust after correction. The HLA-A*11:01-negative/KIR2DS4 Deleted/Deleted profile was associated with higher pretreatment plasma EBV DNA levels in NPC patients, independent of available clinical stage. This finding represents a hypothesis-generating immunogenetic feature linked to baseline EBV DNA heterogeneity, requiring validation in independent cohorts.