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Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

ABSTRACT: We performed bulk RNAseq of HUVECs exposed to cytokine-rich supernatant from T cell dependent cytotoxicity assay with CEA-TCB or DP47-TCB (untargeted-TCB; negative control) to study their activation and contribution to cytokine release.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234668 | GEO | 2023/06/17

REPOSITORIES: GEO

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Project description:These experiments were done as part of a larger study that investigated the mode of action of T-cell bispecific (TCB) antibodies (including CEA-TCB [cibisatamab]) by characterizing molecular and cellular features of immune cells and tumors following TCB treatment in vivo in humanized mice and syngeneic tumor models. To characterize the molecular parameters associated with CEA-TCB treatment we performed bulk RNA sequencing of CEA-TCB-treated and untreated tumors derived from MKN-45 tumor-bearing humanized mice. Tumor tissue was analyzed after seven consecutive TCB treatments and compared to matching controls. RNA sequencing analysis revealed a clear distinction between CEA-TCB-treated and control animals, with several genes being upregulated in tumors treated with CEA-TCB as compared to controls. Among the top 15 upregulated genes in CEA-TCB-treated tumors there were many reflective of a strong T-cell activation, migration, immune cell response (CXCL13, GNLY, GZMB, CXCL10, IDO1, SLA, CD2, TRBC2, TIGIT, IL2RB, CXCL9, CX3CL1, CCL4L2, and CD3E). Among the top downregulated ones we found keratin 6A and keratin 20 (KRT6A and KRT20) suggestive of the reduction of tumor cells as the result of TCB-mediated killing. A Gene Set Enrichment Analysis (GSEA) was conducted that further enabled identification of the main biological pathways upon CEA-TCB treatment and confirmed that the main Gene Ontology families that characterize the TCB response consist of T-cell activation (Response to interferon gamma; Adaptive Immune Response; T-cell activation; Inflammatory Response; Activation of Immune response; Cytokine secretion) and migration (Leukocyte Migration; Regulation of Cell Adhesion). We also noticed upregulation of many major histocompatibility class II molecules that are known to be expressed on antigen presenting cells (HLA-DRA, HLA-DRB5, and HLA-DRB1) along with CX3CL1 (fractalkine, a known monocyte/T-cell attractant molecule) and CSF1 (colony stimulating factor 1, macrophage) suggestive of myeloid cell recruitment and activation at tumor sites post TCB treatment. The signature appeared to be robust, as components of the signature were confirmed using complementary techniques: RNA expression analysis and protein expression as determined by flow cytometry and multiplex analysis.

Dataset Information

Dissecting the mechanisms underlying the Cytokine Release Syndrome (CRS) mediated by T Cell Bispecific Antibodies

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