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Digital spatial profiling uncovers transcriptomic features of distinct plasma cell-like phenotypes in diffuse large
Zucheng Xie1, Yan Qin2, Xuemin Xue3
1Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Diffuse large B-cell lymphoma (DLBCL) exhibits marked heterogeneity, complicating treatment and prognosis. The role of plasma cell-like phenotypes in DLBCL remains underexplored. Using spatially resolved transcriptomics, we profiled 4 distinct plasma cell-like phenotypes in DLBCL based on CD20, HLA-DRA, and PR domain zinc finger protein 1 (PRDM1) markers: CD20+HLA-DRA+ PRDM1-, CD20+ HLA-DRA+ PRDM1+, CD20+ HLA-DRA-PRDM1-, and CD20+ HLA-DRA-PRDM1+. The CD20+ HLA-DRA+ PRDM1- phenotype (nonplasma cell-like phenotype) had better prognosis; the other 3 phenotypes (plasma cell-like phenotypes) had worse prognosis. Patients with >30% plasma cell-like phenotype cells were classified as DLBCL plasma cell-like phenotype predominant (DLBCLPCPP), and those with ≤30% as DLBCL plasma cell-like phenotype deficient (DLBCLPCPD). Plasma cell-like phenotype cells correlated with reduced proliferation, impaired immune function, and enhanced tumor microenvironment remodeling. DLBCLPCPP had lower Ki-67 index of ≥85% (29.6% vs 53.9%, P = .0198), similar first-line response (92.6% vs 92.6%, P = 1.00) but a higher rate of disease progression within 12 months (25.9% vs 3.7%, P = .0238) and more B2M alterations (22.2% vs 3.7%, P = .0509) compared with DLBCLPCPD. Transcriptomic revealed of plasma cell-like phenotype cells to plasmablastic lymphoma. Using phenotype-associated genes, we constructed a random forest model to predict bortezomib response. High plasma cell-like phenotype signatures were linked to poorer progression-free survival (PFS) but greater benefit from R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) plus bortezomib (RB-CHOP), low-signature patients achieved better PFS with R-CHOP alone. These findings characterize the transcriptomic features of distinct plasma cell-like phenotypes in DLBCL, offering new insights for prognostic relevance and individualized treatment strategies.
