Ecto‐calreticulin in immunogenic chemotherapy

Summary: 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 γ‐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.