Digital spatial profiling uncovers transcriptomic features of distinct plasma cell-like phenotypes in diffuse large B-cell lymphoma.

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.