Integrative genomic analysis identifies unique immune environments associated with immunotherapy response in diffuse large B cell lymphoma

Abstract

AbstractMost relapsed or refractory diffuse large B cell lymphoma (DLBCL) patients show primary resistance, or relapse after receiving immunotherapies such as CAR T cells, bispecific antibodies, or checkpoint blockade therapy, highlighting the need for a deeper understanding of mechanisms that regulate the immune environment and response to immunotherapy. Therefore, we performed bulk transcriptomic analysis of 862 diagnostic DLBCL specimens and segregated DLBCLs into four unique quadrants defined by cell-of-origin and immune-related gene set expression scores, termed DLBCL-immune quadrants (DLBCL-IQ). These quadrants consisted of activated B cell-like (ABC) hot, ABC cold, germinal center B cell-like (GCB) hot, GCB cold DLBCLs. Unique genomic alterations were enriched in each immune cluster, suggesting that lymphoma-intrinsic alterations modulate the DLBCL immune environment. For instance,SOCS1loss-of-function mutations were enriched among GCB hot DLBCLs, identifying a putative subset of inflamed DLBCLs that may be inherently susceptible to immunotherapy. Finally, treatment with the CD20 x CD3 bispecific antibody, mosunetuzumab, was associated with significantly improved progression-free survival of GCB hot DLBCL patients, underscoring the importance of our DLBCL-IQs in predicting bispecific antibody efficacy in this disease.SignificanceThis in-depth characterization of DLBCL immune landscapes and associated genomic alterations should catalyze development of rationally designed, combinatorial studies of targeted and immune therapies. Moreover, the association between the immune environment and clinical outcomes to a bispecific antibody is important, and similar analyses can be employed to address how particular DLBCL immune environments influence the efficacy of checkpoint blockade and CAR T cell therapy.