Cytokines in immunogenic cell death: Applications for cancer immunotherapy

Abstract

Despite advances in treatments like chemotherapy and radiotherapy, metastatic cancer remains a leading cause of death for cancer patients. While many chemotherapeutic agents can efficiently eliminate cancer cells, long-term protection against cancer is not achieved and many patients experience cancer recurrence. Mobilizing and stimulating the immune system against tumor cells is one of the most effective ways to protect against cancers that recur and/or metastasize. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN-γ or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. To this end, a group of anthracyclines or treatments like photodynamic therapy (PDT) exert their effects on cancer cells in a manner that activates the immune system. This process, known as immunogenic cell death (ICD), is characterized by the release of membrane-bound and soluble factors that boost the function of immune cells. This review will explore different types of ICD inducers, some in clinical trials, to demonstrate that optimizing the cytokine response brought about by treatments with ICD-inducing agents is central to promoting anti-cancer immunity that provides long-lasting protection against disease recurrence and metastasis.

Keywords: Cancer; Chemotherapeutics; Danger-Associated Molecular Patterns (Damps); Immunotherapy; Stress response.

Figure 1. Cytokines involved in ICD Induction

ICD inducers trigger the release of DAMPs (e.g. HMGB1, Calreticulin, ATP) and inflammatory cytokines from cancer cells. The DAMPs and cytokines signal to dendritic cells and Natural Killer (NK) cells that in turn release effector cytokines. T cells differentiate into cytotoxic lymphocytes (CTLs) or TH1/TH17 cells, releasing additional effector cytokines.