T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

Abstract

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 and 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 we 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. image T cell‐dependent bispecific antibodies induce adverse systemic changes in addition to tumor killing. This study shows how different vascular beds respond to cancer immunotherapy, suggesting that reducing leukocyte‐endothelial interactions may limit the accumulation of T cells, thereby alleviating off‐tumor adverse responses. An in‐depth characterization of acute systemic responses to T cell‐dependent bispecific antibodies is presented. Immunological and vascular responses in the liver are observed that are more striking than the tumor responses. Liver response shows a vascular‐subtype‐dependent pattern. Transcriptional programs and candidate factors are uncovered that could account for the undesirable response.