Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response
Abstract
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.
Article Details
Authors (24)
Sravya Tumuluru
1Weill Cornell Medicine, Hematology and Oncology, New York, United States
James K. Godfrey
2Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA
Alan Cooper
3Yale University School of Medicine, New Haven, United States
Jovian Yu
15AbbVie Inc., North Chicago, United States
Xiufen Chen
3Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
Brendan W. MacNabb
4Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA
Girish Venkataraman
2University of Chicago, Department of Pathology, Illinois, United States
Yuanyuan Zha
Benedikt Pelzer
1Weill Cornell Medicine, Hematology and Oncology, New York, United States
Joo Song
1City of Hope National Medical Center, Department of Hematology and Hematopoietic Cell Transplantation, Duarte, United States
Gerben Duns
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Brian J. Sworder
Sandeep Raj
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Christopher Bolen
11Genentech Inc, South San Francisco, CA
Elicia Penuel
12Genentech, Inc, South San Francisco, CA
Ekaterina Postovalova
Nikita Kotlov
2BostonGene Corporation, Waltham, United States
Aleksander Bagaev
12BostonGene Corporation, Waltham, MA
Nathan Fowler
39Department of Hematology and Oncology, MD Anderson Cancer Center, Houston, TX
Roni Shouval
1Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Sonali M. Smith
3Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL
Ash A. Alizadeh
Christian Steidl
5Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, Canada
Justin Kline
16University of Chicago Comprehensive Cancer Center, Chicago, United States