Integrative analysis of m6A-related genetic variants and single-cell RNA sequencing identifies HLA-DQA1/HLA-DQB1-associated immune signatures in CAR-T-treated diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) shows heterogeneous responses to CAR-T therapy, but the links among m6A-related genetic variation, immune-cell states, and treatment response remain incompletely defined. We integrated FinnGen GWAS summary statistics, RMDisease V2.0 m6A-SNP annotations, eQTL annotation, and single-cell RNA-seq data from CAR-T-treated refractory B-cell lymphoma patients. Eleven DLBCL-associated m6A-SNPs were identified using a suggestive association threshold, and nine had eQTL signals in the HaploReg-based annotation. After distinguishing m6A annotation genes from eQTL target genes and excluding non-coding/intergenic targets, HLA-DQA1 and HLA-DQB1 were prioritized for downstream interpretation. Single-cell analyses showed that these HLA-DQ genes were detectable across immune-cell contexts and were associated with response-related CAR-T cell states, antigen-presentation programs, and MHC class II cell-cell communication. Clinical validation using post-treatment blood samples from responders (n = 15) and non-responders (n = 11) supported response-associated differences in inflammatory cytokines and HLA-DQ-related immune signatures. These findings identify an association-level HLA-DQ-centered immune signature linked to CAR-T treatment response in DLBCL and provide a basis for further mechanistic and prospective validation.