Abstract
Calreticulin (CRT) exposure on the cell surface is essential for inducing immunogenic cell death by chemotherapy. Recent studies have shown conflicting effects of chemotherapy-induced autophagy on CRT exposure in cancer cells. Our data revealed that surface-exposed CRT (Ecto-CRT) emission was attenuated by inhibition of autophagy at early stages; however, inhibition of autophagy at late stages resulted in increased Ecto-CRT. Furthermore, neither autophagy activation nor endoplasmic reticulum (ER) stress induction alone was sufficient for CRT surface exposure. Moreover, chemotherapeutic agents that only activated autophagy without inducing ER stress could not increase Ecto-CRT; therefore, combined use of an autophagy activator and ER stress inducer could effectively promote CRT translocation to the plasma membrane. Together, our results highlight the potential of the combined use of ER stress inducers and autophagy late-stage inhibitors to reestablish and strengthen both the CRT exposure and immunogenicity of chemotherapeutic agents induced death cells.
Highlights
Some chemotherapeutic agents, such as Cyclophosphamide, Doxorubicin, Epirubicin, Mitoxantrone and Oxaliplatin, can induce immunogenic cell death (ICD) of cancer cells [1]; clinically these agents fail to lead to tumor rejection unaffecting prognosis in patients with malignant disease
Autophagy-deficient tumor cells treated with ICD inducers in vitro fail to induce a tumor-specific immune response in vivo because of the inability to release adenosine triphosphate (ATP) [10], enhanced autophagy correlates with activation of antiwww.impactjournals.com/oncotarget tumor immunity and its downregulation may contribute to immune system avoidance in malignant growths
We hypothesized that early stage autophagy activated by low Oxaliplatin dosage may promote CRT exposure; activation from high Oxaliplatin dosage may inhibit CRT exposure
Summary
Some chemotherapeutic agents, such as Cyclophosphamide, Doxorubicin, Epirubicin, Mitoxantrone and Oxaliplatin, can induce immunogenic cell death (ICD) of cancer cells [1]; clinically these agents fail to lead to tumor rejection unaffecting prognosis in patients with malignant disease. Current chemotherapeutic agents are ineffective at triggering ICD of cancer cells at the patient level. Previous reports suggested that autophagy acts as an ‘enabler’ of ICD by assisting in ATP secretion [7], while other studies demonstrated opposing effects of chemotherapy-induced autophagy on CRT exposure in cancer cells. Autophagy was found to suppress the induction of Ecto-CRT [8, 9]; it was shown that autophagy-incompetent tumor cells can escape from chemotherapy-induced immunosurveillance [10]. These conflicting observations illustrate that how autophagy participates and regulates chemotherapy-induced CRT exposure remains unclear
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