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Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response.

Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response. Blood Tumuluru, S., Godfrey, J. K., Cooper, A., Yu, J., Chen, X., MacNabb, B., Venkataraman, G., Zha, Y., Pelzer, B., Song, J. Y., Duns, G., Sworder, B., Raj, S. S., Bolen, C. R., Penuel, E., Postovalova, E., Kotlov, N., Bagaev, A., Fowler, N. H., Shouval, R., Smith, S. M., Alizadeh, A. A., Steidl, C., Kline, J. P. 2025

Abstract

Most diffuse large B-cell lymphoma (DLBCL) patients treated with immunotherapies such as bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was applied to multiple large independent datasets in order to characterize DLBCL immune environments, and to define their association with tumor cell-intrinsic genomic alterations and outcomes to CD19-directed CAR T-cell and CD20 x CD3 BsAb therapies. This approach effectively segregated DLBCLs into four immune quadrants (IQ) defined by cell-of-origin and immune-related gene set expression scores. These quadrants consisted of activated B cell-like (ABC) hot, ABC cold, germinal center B cell-like (GCB) hot, GCB cold DLBCLs. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute significantly to orchestrating unique DLBCL immune environments. For instance, SOCS1 loss-of-function mutations were significantly enriched among GCB hot DLBCLs, identifying a putative subset of inflamed DLBCLs that may be inherently susceptible to immunotherapy. In relapsed/refractory DLBCL patients, DLBCL-IQ assignment correlated significantly with clinical benefit with a CD20 x CD3 BsAb (n = 74), but not with CD19-directed CAR T cells (Stanford, n = 51; MSKCC, n = 69). Thus, DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and suggests the endogenous immune environment has a more significant impact on outcomes to BsAb compared to CAR T cell treatment.

View details for DOI 10.1182/blood.2024025355

View details for PubMedID 39869833