It is commonly assumed that the only goal of anticancer chemotherapy, like antimicrobial antibiotic therapy, is to eradicate by direct cytotoxic effects all tumor cells. According to this mechanism, complete and permanent cure would be obtained by antineoplastic agents that succeed in killing all cancer cells including cancer stem cells and micrometastases. 1,2 In fact, cancer has long been conceived and treated as a cell-autonomous phenomenon, regardless of the immune system's contribution to the therapeutic response. Recently, we have challenged this idea by showing that, at least in the case of anthracyclin-mediated chemotherapy, the antitumor immune response plays a major role in therapeutic success. Thus, immunocompetent mice bearing CT26 colon carcinomas or MCA205 fibrosarcomas can be cured by intratumoral injection of anthracyclins, whereas immunodeficient mice lacking T cells only exhibit partial responses with a delay in tumor growth. [3][4][5] Detailed molecular studies revealed that anthracyclins have the peculiar capacity of inducing immunogenic cell death. In contrast, many other cytotoxic agents including agents that damage nuclear DNA (such as etoposide and mitomycin C), mitochondria, the endoplasmic reticulum or lysosomes fail to induce immunogenic cell Cells were transfected with a control siRNA or a CRT-specific siRNA heteroduplex (sense strand: 5 0 -rCrCrGrCUrGrGrGUrCrGrArAUrCrRrArATT-3 0 ). Thirty-six hours later, the cells were subjected to g-irradiation (g) or UVC light (h), cultured for 4 h, optionally treated with recombinant CRT protein (3 mg/10 6 cells in PBS on ice for 30 min, followed by three washes) and subjected to immunofluorescence staining of CRT as above. (i, j) Requirement of CRT exposure for the immunogenic effect of ionizing irradiation. CT26 colon cancer cells were transfected with the indicated siRNAs, g-irradiation (i), UV light (j) and/or recombinant CRT (as in g and h) and then injected subcutaneously (3 Â 10 6 cells) into the left flank of BALB/c mice. One week after this vaccination, the mice were challenged with live tumor cells in the opposite flank (day 0) and the frequency of tumor-free animals was monitored (mean7S.E.M.); n represents the absolute number of mice enrolled in each cohort. *Po0.001 (Student's t-test)
The conventional treatment of cancer relies upon radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Nonetheless, there are circumstances in which conventional anti-cancer therapy can induce a modality of cellular demise that elicits innate and cognate immune responses, which in turn mediate part of the anti-tumor effect. Although different chemotherapeutic agents may kill tumor cells through an apparently homogeneous apoptotic pathway, they differ in their capacity to stimulate immunogenic cell death. We discovered that the pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells. Thus, anthracyclines and gamma-irradiation that induce ecto-CRT cause immunogenic cell death, while other pro-apoptotic agents (such as mitomycin C and etoposide) induce neither ecto-CRT nor immunogenic cell death. Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, while exogenous supply of CRT or enforcement of CRT exposure by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. For optimal anti-tumor vaccination and immunogenic chemotherapy, the same cells have to expose ecto-CRT and to succumb to apoptosis; if these events affect different cells, no anti-tumor immune response is elicited. These results may have far reaching implications for tumor immunology because (i) ecto-CRT exposure by tumor cells allows for the prediction of therapeutic outcome and because (ii) the re-establishment of ecto-CRT may ameliorate the efficacy of chemotherapy.
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