Concepts and mechanisms underlying chemotherapy induced immunogenic cell death: impact on clinical studies and considerations for combined therapies

Simon Gebremeskel and Brent Johnston _

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Oncotarget. 2015; 6:41600-41619. https://doi.org/10.18632/oncotarget.6113

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Simon Gebremeskel1,4 and Brent Johnston1,2,3,4

1 Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

2 Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada

3 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

4 Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada

Correspondence to:

Brent Johnston, email:

Keywords: cancer therapy, immunostimulation, immunogenic cell death, immunotherapy, chemotherapy

Received: September 03, 2015 Accepted: September 22, 2015 Published: October 14, 2015


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.

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