Hypoxia induces immunogenic cell death of cancer cells by enhancing the exposure of cell surface calreticulin in an endoplasmic reticulum stress-dependent manner

Abstract

Hypoxia is associated with resistance to anticancer therapies. Additionally, it is involved in the immune evasion of cancer cells by inducing an immunosuppressive microenvironment. However, the role of hypoxia in modulating the immunogenicity of cancer cells remains unknown. Hypoxia is known to induce endoplasmic reticulum (ER) stress, which serves a key role in inducing the cell surface exposure of calreticulin, a marker of immunogenic cell death. The present study investigated whether hypoxia influenced the immunogenicity of cancer cells using FACS, western blot analysis and syngenic mouse tumor model. The results revealed that hypoxia induced the cell surface exposure of calreticulin in human and mouse breast cancer cell lines depending on ER stress. Enhanced cell surface exposure of calreticulin induced by hypoxia resulted in an increase in anticancer immunity in a mouse model, which suggested that hypoxia induced immunogenic cell death. Notably, hypoxia did not significantly modulate the cell surface exposure of CD47, an antagonist of calreticulin function in cancer immunogenicity. These results suggest that hypoxia may enhance the immunogenicity of cancer cells themselves, in addition to its role in inducing an immunosuppressive cancer microenvironment.