Exploring CAR‐T Resistance Mechanisms in Relapsed/Refractory DLBCL via Integrated Histopathological and Transcriptomic Profiling
Wei Li, Yang Li, Qian Li, Rui Cui, Wei‐Na Guo, Cheng‐Cheng Yan, Zhan‐Dong Hu, Yu‐Jie Zhang, Wei‐Wei Xin, Zhi‐Qi Yin, Xue‐Xi Guo, Ming‐Fang Zhang, Wen‐Juan Cai, Qi DengABSTRACT
In this hypothesis‐generating study, we integrated histopathology and transcriptomics in six patients with relapsed/refractory diffuse large B‐cell lymphoma (R/R DLBCL) receiving anti‐CD19 CAR‐T therapy, stratified into CAR‐T‐responsive and CAR‐T‐resistant cohorts by clinical response. Resistant tumors exhibited diffuse growth patterns with cohesive blast sheets, centroblastic morphology, tumor necrosis, and an immune‐desert tumor microenvironment. Transcriptomics revealed three transcriptional programs that may correlate with CAR‐T resistance: pro‐fibrotic/extracellular matrix remodeling, proliferative and pro‐survival traits, and immune dysfunction. Exploratory integrative analysis indicated associations between morphological features and pre‐existing pathway dysregulation in CAR‐T‐resistant patients, such as hyperactivated PI3K–Akt–mTOR and impaired antigen presentation. Collectively, these observations imply CAR‐T resistance in R/R DLBCL may stem from synergistic interplay among morphological aberrations, dysregulated proliferative/stromal pathways, and local immunosuppression. Pending prospective validation in larger independent cohorts, the candidate biomarkers observed herein may aid outcome prediction and combinatorial regimen design for R/R DLBCL.