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Integrated Transcriptomic and Proteomic Dynamics of Rituximab Treatment in B Lymphoblastoid Cells

ABSTRACT: The investigation aims to profile the molecular dynamics of Rituximab treatment in cells. Specifically, a B-lymphoblast cells line was treated with Rituximab, and sampled every hour over a 24hour period. Treated and untreated cells were processed to extract RNA and protein that were subsequently used in high-throughput analysis of the transcriptome (RNA-Sequencing) and proteome (mass spectrometry). We expect our approach not only to provide a unique reference dataset to the scientific community but to also act as a paradigm as an approach to identify novel transcriptome-proteome molecular markers utilized in mapping drug action pathways. We have identified specific expression at both the gene and protein levels and are inferring associations between the omics through the use of temporal pattern identification, thus defining time-varying networks. This study will provide the next steps in the development of reference dynamic omics data that may be used in creating integration models, with further applications in dynamic monitoring of samples in precision medicine implementation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89062 | GEO | 2017/09/15

SECONDARY ACCESSION(S): PRJNA350221

REPOSITORIES: GEO

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Project description:Purpose: Despite recent advances in the treatment of patients with aggressive lymphomas, still a significant fraction of patients will succumb to their disease. Thus, novel therapeutic strategies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Experimental Design: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Overall, three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 2/11 cell lines were primarily sensitive to tafasitamab and 2/11 were predominantly sensitive to rituximab treatment, the combination of tafasitamab and rituximab resulted in enhanced cell death in 7/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combinatorial approach of the two antibodies resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusions: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to antibody mono treatment in models of aggressive B-cell lymphoma in vitro and in vivo. Translational Relevance: The immunochemotherapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard of care for newly diagnosed DLBCL patients. However, 30-40% of patients are refractory or relapse after initial response to the immunochemotherapy, indicating a high-unmet medical need for these patients. Tafasitamab and rituximab target the B-cell surface proteins CD19 and CD20, respectively, and both antibodies feature overlapping modes of action , namely direct cytotoxicity, ADCC and ADCP. In this study, we show that the combination of tafasitamab and rituximab had additive and synergistic efficacy both in vitro and in vivo. Our findings shed new light on the underlying mechanism of the combination of both antibodies and lay the ground to translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.

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Integrated Transcriptomic and Proteomic Dynamics of Rituximab Treatment in B Lymphoblastoid Cells

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