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

Tumuluru, S.; Godfrey, J. K.; Cooper, A.; Yu, J.; Chen, X.; MacNabb, B. W.; Venkataraman, G.; Zha, Y.; Pelzer, B.; Song, J.; Duns, G.; Bolen, C.; Penuel, E.; Postovalova, E.; Kotlov, N.; Bagaev, A.; Fowler, N.; Smith, S. M.; Steidl, C.; Kline, J.

doi:10.1101/2024.01.17.576100

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bioRxiv · 10.1101/2024.01.17.576100

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

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Abstract

Most diffuse large B-cell lymphoma (DLBCL) patients treated with 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 employed to characterize DLBCL immune environments, which effectively segregated DLBCLs into four quadrants - termed DLBCL-immune quadrants (IQ) - defined by cell-of-origin and immune-related gene set expression scores. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute to orchestrating unique DLBCL immune environments. In relapsed/refractory DLBCL patients, DLBCL-IQ assignment correlated significantly with clinical benefit with the CD20 x CD3 BsAb, mosunetuzumab, but not with CD19-directed CAR T cells. DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and uncovers the differential impact of the endogenous immune environment on outcomes to BsAb and CAR T cell treatment.

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Tumuluru, S., Godfrey, J. K., Cooper, A., Yu, J., Chen, X., MacNabb, B. W., Venkataraman, G., Zha, Y., Pelzer, B., Song, J., Duns, G., Bolen, C., Penuel, E., Postovalova, E., Kotlov, N., Bagaev, A., Fowler, N., Smith, S. M., Steidl, C., Kline, J.. 2024-01-22. Integrative genomic analysis identifies unique immune environments associated with immunotherapy response in diffuse large B cell lymphoma. https://doi.org/10.1101/2024.01.17.576100

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