Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies.
Chemotherapy has historically been thought to induce cancer cell death in an immunogenically silent manner. However, recent studies have demonstrated that therapeutic outcomes with specific chemotherapeutic agents (e.g. anthracyclines) correlate strongly with their ability to induce a process of immunogenic cell death (ICD) in cancer cells. This process generates a series of signals that stimulate the immune system to recognize and clear tumor cells. Extensive studies have revealed that chemotherapy-induced ICD occurs via the exposure/release of calreticulin (CALR), ATP, chemokine (C-X-C motif) ligand 10 (CXCL10) and high mobility group box 1 (HMGB1). This review provides an in-depth look into the concepts and mechanisms underlying CALR exposure, activation of the Toll-like receptor 3/IFN/CXCL10 axis, and the release of ATP and HMGB1 from dying cancer cells. Factors that influence the impact of ICD in clinical studies and the design of therapies combining chemotherapy with immunotherapy are also discussed.
Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Simon
S
Gebremeskel
Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.|Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
Brent
B
Johnston
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064032:Calbindin 2 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007370:Interferon Type I / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D019139:Tumor Escape
D064032:Calbindin 2; D024243:HMGB1 Protein; D007370:Interferon Type I; D051196:Toll-Like Receptor 3; D000255:Adenosine Triphosphate
cancer therapy; chemotherapy; immunogenic cell death; immunostimulation; immunotherapy