%0 Journal Article
%T Calreticulin and type I interferon: An unsuspected connection
%A Guido Kroemer
%A Lorenzo Galluzzi
%J Archive of "Oncoimmunology".
%D 2017
%R 10.1080/2162402X.2017.1288334
%X Calreticulin (CALR, also known as CRT) is a chaperone of the endoplasmic reticulum (ER) involved in the maintenance of reticular homeostasis and the presentation of MHC class I antigens.1,2 In addition, CRT is actively translocated to the outer leaflet of the plasma membrane by cancer cells that die in response to some (but not all) stimuli, including specific chemotherapeutics (e.g., doxorubicin, mitoxantrone, oxaliplatin, bortezomib), hypericin-based photodynamic therapy and ionizing irradiation.3-5 In all these settings, CRT exposure on the cell surface is required for dying cells to elicit an adaptive immune response specific for dead cell-associated antigens and associated with the development of immunological memory.6 Thus, wild-type murine cancer cells undergoing such an immunogenic variant of cellular demise ¨C which is commonly known as ˇ°immunogenic cell deathˇ± (ICD) ¨C can be used to efficiently vaccinate syngeneic immunocompetent mice against a subsequent challenge with live cells of the same type.7 Conversely, murine cancer cells that have been depleted of CRT by specific small-interfering RNAs and killed with ICD inducers are unable to elicit protective immunity upon inoculation into syngeneic immunocompetent hosts, a defect that can be corrected by the adsorption of recombinant CRT to the surface of dying cells.8 In line with this notion, spontaneous or therapy-driven CRT exposure by malignant cells has been linked with improved disease outcome in cohorts of acute myeloid leukemia (AML) and non-small cell lung carcinoma (NSCLC) patients.9-11 Of note, the immunostimulatory activity of CRT exposed on dying cancer cells has largely been attributed to its ability to operate as an ˇ°eat-meˇ± signal,12 hence favoring the uptake of cell corpses by phagocytes expressing LDL receptor-related protein 1 (LRP1; also known as CD91).13,14 Until now, however, CRT exposure has been mostly studied in the context of ICD, which is associated with secretion of several other danger signals, including ATP, high-mobility group box 1 (HMGB1), annexin A1 (ANXA1), and type I interferon (IFN).6 To eliminate these potential confounders from the analysis, Chen and colleagues generated murine AML cells stably expressing CRT on the outer leaflet of the plasma membrane and compared them with WT cells for immunostimulatory and pathogenic potential in vivo.15 Unsuspectedly, the capacity of CRT-exposing AML cells to initiate a protective anticancer immune response did not correlate with increased phagocytosis but was linked to type I IFN signaling.15 These data highlight an
%K Acute myeloid leukemia
%K ATP
%K CD8+ cytotoxic T lymphocytes
%K dendritic cells
%K HMGB1
%K immunogenic cell death
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384383/