T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198869 | GEO | 2022/12/09
REPOSITORIES: GEO
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Project description:TDBs (T cell dependent bispecific antibodies) have an agonistic anti-CD3 arm paired with a tumor-targeting arm that recognizes tumor-restricted/enriched cell-surface proteins. Preclinical and clinical studies demonstrated that TDBs can induce systemic changes in addition to their expected action in tumors, including transient loss of circulating leukocytes (margination), systemic cytokine release, and accumulation of lymphocytes in normal tissues. These reactions can lead to undesirable symptoms including cytokine release syndrome and liver enzyme elevation. Here, we report for the first-time an in-depth characterization of acute responses in tumor and liver upon TDB treatment. We observed rapid and substantial accumulation of lymphocytes around large blood vessels in normal organs such as the liver, accompanied by elevated vascular endothelial cell (EC) activation markers. We hypothesized that organ-specific EC phenotypes may account for the differential T cell accumulation in normal tissues versus tumors. Despite ongoing efforts to better characterize specific properties of ECs, the underlying transcriptional changes of specific endothelial cell subtypes influencing the T cell trafficking and accumulation in non-target-expressing organs (like here liver) upon TDB treatment are unknown. The purpose of the study is to investigate the effect of anti-HER2/CD3 TDB treatment on the endothelial cells in the liver and characterize possible transcriptional changes occurring.
2022-12-09 | GSE198868 | GEO
Project description:TDBs (T cell dependent bispecific antibodies) have an agonistic anti-CD3 arm paired with a tumor-targeting arm that recognizes tumor-restricted/enriched cell-surface proteins. Preclinical and clinical studies demonstrated that TDBs can induce systemic changes in addition to their expected action in tumors, including transient loss of circulating leukocytes (margination), systemic cytokine release, and accumulation of lymphocytes in normal tissues. These reactions can lead to undesirable symptoms including cytokine release syndrome and liver enzyme elevation. Here, we report for the first-time an in-depth characterization of acute responses in tumor and liver upon TDB treatment. We observed rapid and substantial accumulation of lymphocytes around large blood vessels in normal organs such as the liver, accompanied by elevated vascular endothelial cell (EC) activation markers. We hypothesized that organ-specific EC phenotypes may account for the differential T cell accumulation in normal tissues versus tumors. Despite ongoing efforts to better characterize specific properties of ECs, the underlying transcriptional changes of specific endothelial cell subtypes influencing the T cell trafficking and accumulation in non-target-expressing organs (like here liver) upon TDB treatment are unknown. The purpose of the study is to investigate the effect of anti-HER2/CD3 TDB treatment on the endothelial cells in the liver and characterize possible transcriptional changes occurring.
2022-12-09 | GSE198867 | GEO
Project description:Preclinical and clinical studies demonstrate that T cell-dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an in-depth characterization of acute responses to TDBs in tumor-bearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation as well as endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ-specific ECs may account for the differential responses in normal tissues and tumors, and identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM 1 to support T cell-EC interaction in response to soluble factors released from a TDB-mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB-mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy.
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