Abstract
Purpose: Tumor-infiltrating B lymphocytes (TIL-B) have demonstrated prognostic and predictive significance in solid cancers. In this study, we aimed to distinguish TIL-Bs from malignant B-cells in diffuse large B-cell lymphoma (DLBCL) and determine the clinical and biological significance. Experimental Design: A total of 269 patients with de novo DLBCL from the International DLBCL R-CHOP Consortium Program were studied. Ultra-deep sequencing of the immunoglobulin genes was performed to determine B-cell clonotypes. The frequencies and numbers of TIL-B clonotypes in individual repertoires were correlated with patient survival, gene expression profiling (GEP) data, and frequencies of DLBCL-infiltrating immune cells quantified by fluorescent multiplex IHC at single-cell resolution. Results: TIL-B abundance, evaluated by frequencies of normal B-cell clonotypes in the immunoglobulin repertoires, remarkably showed positive associations with significantly better survival of patients in our sequenced cohorts. DLBCLs with high versus low TIL-B abundance displayed distinct GEP signatures, increased prememory B-cell state and naïve CD4 T-cell state fractions, and higher CD4+ T-cell infiltration. TIL-B frequency, as a new biomarker in DLBCL, outperformed the germinal center (GC) B-cell–like/activated B-cell–like classification and TIL-T frequency. The identified TIL-B–high GEP signature, including genes upregulated during T-dependent B-cell activation and those highly expressed in normal GC B cells and T cells, showed significant favorable prognostic effects in several external validation cohorts. Conclusions: TIL-B frequency is a significant prognostic factor in DLBCL and plays a crucial role in antitumor immune responses. This study provides novel insights into the prognostic determinants in DLBCL and TIL-B functions with important therapeutic implications.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4808-4821 |
| Number of pages | 14 |
| Journal | Clinical Cancer Research |
| Volume | 29 |
| Issue number | 23 |
| DOIs | |
| State | Published - 2023 |
Funding
G. Bhagat reports personal fees from Blueprint Medicines outside the submitted work. A. Chiu reports personal fees from AstraZeneca outside the submitted work. E.D. Hsi reports grants from Eli Lilly, and Virtuoso Therapeutics, as well as personal fees from Novartis outside the submitted work. I. Kirsch reports personal fees from Adaptive Biotechnologies during the conduct of the study, as well as personal fees from Adaptive Biotechnologies outside the submitted work. No disclosures were reported by the other authors. This study was supported by grants R01CA233490, R01CA187415, R01CA138688, and RC1CA146299 from the NCI/NIH. K.H. Young was also supported by The Duke University Institutional Research Grant Award and the Hagemeister Lymphoma Foundation.
ASJC Scopus subject areas
- General Medicine
