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

• DLBCL-IQ identifies four immune quadrants that are recurrently associated with specific genomic alterations.

• DLBCL-IQ suggests the endogenous immune environment may have a more significant impact on outcomes to BsAb compared to CAR T cell therapy.

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.