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

Most patients with diffuse large B-cell lymphoma (DLBCL) treated with immunotherapies such as bispecific antibodies (BsAbs) 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 multiomics approach was applied to multiple large independent data sets 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 × CD3 BsAb therapies. This approach effectively segregated DLBCLs into 4 immune quadrants (IQs) 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, and 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 patients with relapsed/refractory DLBCL, DLBCL-IQ assignment correlated significantly with clinical benefit with a CD20 × CD3 BsAb (N = 74), but not with CD19-directed CAR T cells (Stanford, N = 51; Memorial Sloan Kettering Cancer Center, 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 than CAR T-cell treatment.

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Journal
Blood
Published
2025-01-27
DOI
https://doi.org/10.1182/blood.2024025355
Citations
15
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
14.64
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article

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

Sravya Tumuluru, Sonali M. Smith, Ash A. Alizadeh, Justin Paul Kline et al.
15 citations
Blood
CAR-T cell therapy research
14.64
article

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

Sravya Tumuluru, Sonali M. Smith, Ash A. Alizadeh, Justin Paul Kline, James Godfrey, Benedikt W. Pelzer, Ekaterina Postovalova, Joo Y. Song, Roni Shouval, Girish Venkataraman, Nathan Fowler, Alexander Bagaev, Christian Steidl, Sandeep S. Raj, Brian J. Sworder, Xiufen Chen, Jovian Yu, Alan Cooper, Yuanyuan Zha, Christopher R. Bolen, Brendan W. MacNabb, Nikita Kotlov, Elicia Penuel, Gerben Duns
article en
15 citations

Abstract

Most patients with diffuse large B-cell lymphoma (DLBCL) treated with immunotherapies such as bispecific antibodies (BsAbs) 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 multiomics approach was applied to multiple large independent data sets 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 × CD3 BsAb therapies. This approach effectively segregated DLBCLs into 4 immune quadrants (IQs) 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, and 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 patients with relapsed/refractory DLBCL, DLBCL-IQ assignment correlated significantly with clinical benefit with a CD20 × CD3 BsAb (N = 74), but not with CD19-directed CAR T cells (Stanford, N = 51; Memorial Sloan Kettering Cancer Center, 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 than CAR T-cell treatment.

BloodVol. 145(21)
California Institute of Technology (US), BC Cancer Agency (CA), City Of Hope National Medical Center (US), Amgen (United States) (US), Memorial Sloan Kettering Cancer Center (US), University of British Columbia (CA), Palo Alto University (US), University of California, Irvine (US), Cornell University (US), Spinal Cord Injury BC (CA), AbbVie (United States) (US), University of Chicago (US), University of Chicago Medical Center (US), Addgene (US), City of Hope (US), Stanford Medicine (US), Weill Cornell Medicine (US), Repligen (United States) (US), Stanford University (US)
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