Human Tumor Cells Killed by Anthracyclines Induce a Tumor-Specific Immune Response

Abstract

Immunogenic cell death is characterized by the early surface exposure of chaperones including calreticulin and HSPs, which affect dendritic cell (DC) maturation and the uptake and presentation of tumor antigens. It has also been shown that it is characterized by the late release of high mobility group box 1 (HMGB1), which acts through Toll-like receptor 4 (TLR4) and augments the presentation of antigens from dying tumor cells to DCs. Most of the data on immunogenic tumor cell death were obtained using mouse models. In this study, we investigated the capacity of clinically used chemotherapeutics to induce immunogenic cell death in human tumor cell lines and primary tumor cells. We found that only anthracyclines induced a rapid translocation of calreticulin, HSP70, and HSP90 to the cell surface and the release of HMGB1 12 hours after the treatment. The interaction of immature DCs with immunogenic tumor cells led to an increased tumor cell uptake and induces moderate phenotypic maturation of DCs. Killed tumor cell-loaded DCs efficiently stimulated tumor-specific IFN-g-producing T cells. DCs pulsed with killed immunogenic tumor cells also induced significantly lower numbers of regulatory T cells than those pulsed with nonimmunogenic tumor cells. These data indicate that human prostate cancer, ovarian cancer, and acute lymphoblastic leukemia cells share the key features of immunogenic cell death with mice tumor cells. These data also identify anthracyclines as anticancer drugs capable of inducing immunogenic cell death in sensitive human tumor cells. Cancer Res; 71(14); 4821-33. Ó2011 AACR.

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

“…[35][36][37] Here, we report the unexpected finding that CRT exposure is regulated not only by cell-intrinsic mechanisms, but also by soluble factors that operate in an autocrine/paracrine manner. When a haploid S. cerevisiae cell is ready to mate, it secretes pheromones that signal cells of the opposite mating type to stop proliferating and prepare for sexual reproduction.…”

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…2 Subsequent studies by us and others identified various mechanisms that underlie not only the ability of a specific stimulus to trigger bona fide ICD as opposed to a non-immunogenic instance of apoptosis, but also the capacity of the host to detect ICD and hence mount a therapeutically relevant immune response against dying cells. 1, [3][4][5][6] Schematically, ICD itself relies on the coordinated emission of a series of damage-associated molecular patterns (DAMPs), [7][8][9][10][11][12] including the exposure of endoplasmic reticulum (ER) chaperones on the cell surface, the secretion of ATP and the release of the non-histone chromatin-binding protein high mobility group box 1 (HMGB1), [13][14][15][16][17][18][19][20] and immunostimulatory cytokines, such as type I interferons. 21 When emitted in the correct spatiotemporal pattern, [22][23][24] such DAMPs recruit antigen-presenting cells, including dendritic cells, to the site of ICD and activate them to engulf dead cell-associated antigens, process and present them to CD4 C and CD8 C T lymphocytes in the context of co-stimulatory signals, resulting in the priming of a robust, antigen-specific immune response.…”

“…[46][47][48] So far, only a few stimuli have been ascribed with the ability to trigger ICD, encompassing both chemical and physical agents. 3,36 Interestingly, such bona fide ICD inducers include various anticancer chemotherapeutics that have been successfully employed in the clinic for several years (Table 1), like (1) doxorubicin, an anthracycline approved by the US Food and Drug Administration (FDA) for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), breast carcinoma, gastric cancer, lymphoma, multiple myeloma (MM), neuroblastoma, ovarian carcinoma, small cell lung carcinoma, soft tissue and bone sarcomas, thyroid carcinoma, transitional cell bladder carcinoma and Wilms' tumor; 2,49 (2) epirubicin, an anthracycline licensed for use in breast carcinoma patients; 2,49 (3) idarubicin, an anthracycline currently employed for the treatment of AML; 19,49 (4) mitoxantrone, an anthracenedione licensed for use in individuals with AML, breast carcinoma, nonHodgkin's lymphoma (NHL) and prostate carcinoma; 2,49 (5) bleomycin, a glycopeptide antibiotic commonly employed as a palliative treatment for Hodgkin's lymphoma, NHL, penile cancer, testicular cancer, and squamous carcinomas of the head and neck, cervix and vulva; 50 (6) bortezomib, a proteasomal inhibitor approved for use in subjects with MM and mantle cell lymphoma; 17,51,52 (7) cyclophosphamide, an alkylating agent nowadays employed for the treatment of ALL, AML, chronic lymphocytic leukemia, breast carcinoma, chronic myeloid leukemia (CML), lymphoma, MM, mycosis fungoides, neuroblastoma, ovarian carcinoma and retinoblastoma; 53 and (8) oxaliplatin, a platinum derivative approved for use in combination with 5-fluorouracil and folinic acid for the therapy of advanced colorectal carcinoma. 40,44,54 Moreover, at least in some cell types, ICD can be provoked by patupilone, an experimental microtubular inhibitor of the epothilone family, [55][56][57] and by 7A7, a monoclonal antibody (mAb) targeting the murine epidermal growth factor receptor (EGFR).…”

Enlightening the impact of immunogenic cell death in photodynamic cancer therapy

“…Moreover, Garg et al (2012) demonstrate that Hyp-PDT stimulates ICD via signalling pathways that overlap with-but are not identical to-those elicited by anthracyclines, which constitute the first ICD inducers to be characterized (Casares et al, 2005;Zappasodi et al, 2010;Fucikova et al, 2011).…”