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.

Hypoxia-Driven Immune Escape in the Tumor Microenvironment

“…CR, a resident chaperon protein predominantly located in the endoplasmic reticulum (ER), is of particular interest when it comes to hypoxia. Han and colleagues recently showed that hypoxia induces cell surface exposure of CR in human and murine breast cancer cell lines, in an ER stress-dependent manner [7]. In line with these findings, Olin and colleagues hypothesized that reducing oxygen tension when culturing tumor cells would increase the efficacy of tumor cell lysate vaccines [69].…”

“…While malignant cells are able to continue to grow and even thrive in the resultant hypoxic microenvironment, it creates inhospitable conditions for immune cells and dampens the response of key regulatory pathways, resulting in immunosuppression [3]. Interestingly, while it is well established in the literature that hypoxia contributes to a diminishing immune response [4][5][6], it has also been shown to simultaneously play an immunostimulatory role, as the consequential pro-inflammatory environment lends to cells dying in an immunogenic manner [7]. This paper discusses the complex and opposing roles of hypoxia signaling in driving immune escape, promoting tumor growth and metastatic potential, while also enhancing certain immunogenic features of the tumor microenvironment (TME).…”

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

“…Hypoxia is known to be an important factor causing drug resistance and immune evasion. It induces ER stress leading to ICD via CRT exposure in human and mouse breast cancer cell lines, suggesting that it enhances the immunogenicity of breast cancer cells in the immunosuppressive tumor microenvironment [ 125 ]. UPR activation is an important feature of tumor development, associated with the ability to acquire essential features such as tumor dormancy, drug resistance, and tumor angiogenesis [ 126 ].…”

Nanoenabled Tumor Oxygenation Strategies for Overcoming Hypoxia-Associated Immunosuppression

“…Tumor hypoxia and overexpression of hydrogen peroxide (H 2 O 2 ) are typical hallmarks of TME. − As is common sense, H 2 O 2 can be catalytically decomposed into O 2 and water. The generated endogenous O 2 is useful for overcoming hypoxia-associated immunosuppressive TME.…”