Enhancing anti-cancer immunity through immunogenic cell death:

the role of endothelial cells in the tumor microenvironment

Immunogenic cell death (ICD) holds promise in cancer immunotherapy by eliminating cancer cells while activating anti-cancer immunity and establishing long-term immunological memory. However, hurdles to effective clinical use arise from the prevalent immunosuppressive milieu within the tumor microenvironment (TME). While professional antigen-presenting cells (APCs) have been extensively studied, the role of non-professional APCs, such as endothelial cells (ECs), remains neglected. Despite their association with tumor growth via angiogenesis, ECs also act as immunomodulators reinforcing ICD’s efficiency. This study aims to unravel the immunomodulatory role of ECs during ICD-based immunotherapy.

In this research, efferocytosis efficiency of ECs and EC activation were assessed. RNA sequencing was performed to characterize the response of ECs to ICD. In addition, a tumor prophylactic vaccination mice model was used to analyze the role of ECs in activating adaptive immunity against ICD-undergoing cancer cells.

Our findings reveal that ECs efficiently engulf ICD-induced cancer cells, leading to EC activation, release of pro-inflammatory cytokines, and upregulation of MHC-I and co-stimulatory signals such as CD80. In vivo, prophylactic tumor vaccination with ECs cultured with dying cancer cells significantly increases tumor-free mice survival. These results highlight for the first time the pivotal role of ECs as favorable immunomodulators during ICD-based anti-cancer immunity.