3 Normally, CRT is present in the lumen of the endoplasmic reticulum (ER). Knockdown of CRT, blockade of ecto-CRT or inhibition of the pathway leading to CRT exposure abolishes the immunogenicity of cell death elicited by anthacyclins or oxaliplatin. 4 Of note, the vast majority cytotoxic agents fail to induce CRT exposure, while only a few such as anthracyclines and oxaliplatin are able to induce ecto-CRT. Membrane-exposed ecto-CRT favors the engulfment of the apoptotic bodies by dendritic cells (DCs), while HMGB1 and ATP modulate DC-mediated tumor antigen presentation and T-cell polarization. The immunogenicity of cell death relies on at least three independent events, namely (i) the early exposure of calreticulin (CRT) on the cell surface of stressed cells (ecto-CRT) 3 and the subsequent (ii) adenosine tri-phosphate (ATP) 4 secretion and (iii) high mobility group box 1 (HMGB1) release 5 by dying tumor cells. These studies unraveled the molecular mechanisms that distinguish immunogenic from non-immunogenic cell death. 2 However, a recent series of papers has demonstrated that some chemotherapeutic agents, in particular anthracyclines and oxaliplatin, are unique in their capacity to induce immunogenic cancer cell death in mice. Indeed, billions of cells succumb to apoptosis every day in healthy individuals yet do not provoke any signs of autoimmunity. 1 Moreover, apoptosis seems to be the principal cell death mechanism induced by chemotherapy, and apoptosis is mostly viewed as a non-immunogenic (or even tolerogenic) cell death modality. Owing to this immunosuppressive side effect, it is intrinsically difficult to elicit immune responses against tumor antigens in patients after several cycles of chemotherapy. One strategy that might improve therapeutic outcome relies on combination of potent cytotoxic chemotherapeutics and the induction of antitumor immune responses that control residual disease.Īt the theoretical level, chemotherapy and immunotherapy are difficult to be reconciled because chemotherapy with DNA-damaging agents often induces the massive destruction of immune effectors. However, we know that a long-lasting disease-free survival is not easy to achieve, presumably because some tumor (stem) cells escape from therapy and may remain dormant for months, years and sometimes decades. We conclude that the presence of ecto-CRT on leukemia cells facilitates cellular anticancer immune responses in AML patients.Īn optimally efficient anticancer therapy can be achieved by destroying each cancer cell. Importantly, high levels of ecto-CRT on malignant myeloblasts positively correlated with the ability of autologous T cells to secrete interferon- γ on stimulation with blast-derived dendritic cell. Ecto-CRT correlated with the presence of phosphorylated eIF2 α within the blasts, in line with the possibility that CRT exposure results from an endoplasmic reticulum stress response. We observed that leukemic cells from some patients exhibited ecto-CRT regardless of chemotherapy and that this parameter was not modulated by in vivo chemotherapy. In this study, we investigated ecto-CRT expression on malignant blasts before and after induction chemotherapy. Most of the patients benefit from the induction chemotherapy but relapse within 1–12 months. Here, we determined whether CRT exposure at the cell surface (ecto-CRT) occurs in human cancer in response to anthracyclines in vivo, focusing on acute myeloid leukemia (AML), which is currently treated with a combination of aracytine and anthracyclines. Experiments performed in mice revealed that anthracyclines stimulate immunogenic cell death that is characterized by the pre-apoptotic exposure of calreticulin (CRT) on the surface of dying tumor cells.
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