The concept of immunogenic cancer cell death (ICD), as originally observed during the treatment with several chemotherapeutics or ionizing irradiation, has revolutionized the view on the development of new anticancer therapies. ICD is defined by endoplasmic reticulum (ER) stress response, reactive oxygen species (ROS) generation, emission of danger-associated molecular patterns and induction of antitumor immunity. Here we describe known and emerging cancer cell death-inducing physical modalities, such as ionizing irradiation, ultraviolet C light, Photodynamic Therapy (PDT) with Hypericin, high hydrostatic pressure (HHP) and hyperthermia (HT), which have been shown to elicit effective antitumor immunity. We discuss the evidence of ICD induced by these modalities in cancer patients together with their applicability in immunotherapeutic protocols and anticancer vaccine development.

Cell Death Research and Therapy ; Leuven Belgium

Sotio ; Prague Czech Republic ; Department of Immunology; 2nd Faculty of Medicine and University Hospital Motol; Charles University ; Prague Czech Republic

Zobrazit více v PubMed

Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol, Biol, Phys 2004; 58:862-70; PMID:; http://dx.doi.org/10.1016/j.ijrobp.2003.09.012 PubMed DOI

Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol 1953; 26:234-41; PMID:; http://dx.doi.org/10.1259/0007-1285-26-305-234 PubMed DOI

Korbelik M, Krosl G, Krosl J, Dougherty GJ. The role of host lymphoid populations in the response of mouse EMT6 tumor to photodynamic therapy. Cancer Res 1996; 56:5647-52; PMID: PubMed

Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005; 202:1691-701; PMID:; http://dx.doi.org/10.1084/jem.20050915 PubMed DOI PMC

Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13:54-61; PMID:; http://dx.doi.org/10.1038/nm1523 PubMed DOI

Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, Ortiz C, Lidereau R, Mariette C, Chaput N, Mira JP, Delaloge S, et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev 2007; 220:47-59; PMID:; http://dx.doi.org/10.1111/j.1600-065X.2007.00573.x PubMed DOI

Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 2007; 13:1050-9; PMID:; http://dx.doi.org/10.1038/nm1622 PubMed DOI

Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature 2000; 407:784-8; PMID:; http://dx.doi.org/10.1038/35037722 PubMed DOI

Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998; 392:86-9; PMID:; http://dx.doi.org/10.1038/32183 PubMed DOI

Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, Frelinger JA, Robinson BW, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 2003; 170:4905-13; PMID:; http; http://dx.doi.org/10.4049/jimmunol.170.10.4905 PubMed DOI

Guo ZS, Liu Z, Bartlett DL. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity. Front Oncol 2014; 4:74; PMID:; http://dx.doi.org/10.3389/fonc.2014.00074 PubMed DOI PMC

Inoue H, Tani K. Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. Cell Death Differ 2014; 21:39-49; PMID:; http://dx.doi.org/10.1038/cdd.2013.84 PubMed DOI PMC

Koks CA, Garg AD, Ehrhardt M, Riva M, Vandenberk L, Boon L, Vleeschouwer SD, Agostinis P, Graf N, Van Gool SW. Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death. Int J Cancer 2015; 136:E313-E325; PMID:25208916; http://dx.doi.org/10.1002/ijc.29202 PubMed DOI

Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, van Endert P, Zitvogel L, Kroemer G. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ 2007; 14:1848-50; PMID:; http://dx.doi.org/10.1038/sj.cdd.4402201 PubMed DOI

Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, Durchschlag M, Joza N, Pierron G, van Endert P, et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 2009; 28:578-90; PMID:; http://dx.doi.org/10.1038/emboj.2009.1 PubMed DOI PMC

Garg AD, Krysko DV, Vandenabeele P, Agostinis P. The emergence of phox-ER stress induced immunogenic apoptosis. Oncoimmunology 2012; 1:786-8; PMID:; http://dx.doi.org/10.4161/onci.19750 PubMed DOI PMC

Kepp O, Menger L, Vacchelli E, Locher C, Adjemian S, Yamazaki T, Martins I, Sukkurwala AQ, Michaud M, Senovilla L, et al. Crosstalk between ER stress and immunogenic cell death. Cytokine Growth Factor Rev 2013; 24:311-8; PMID:; http://dx.doi.org/10.1016/j.cytogfr.2013.05.001 PubMed DOI

Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukocyte Biol 2007; 81:1-5; PMID:; http://dx.doi.org/10.1189/jlb.0306164 PubMed DOI

Matzinger P. Tolerance, danger, and the extended family. Ann Rev Immunol 1994; 12:991-1045; PMID:; http://dx.doi.org/10.1146/annurev.iy.12.040194.005015 PubMed DOI

Garg AD, Martin S, Golab J, Agostinis P. Danger signalling during cancer cell death: origins, plasticity and regulation. Cell Death Differ 2014; 21:26-38; PMID:; http://dx.doi.org/10.1038/cdd.2013.48 PubMed DOI PMC

Garg AD, Dudek AM, Agostinis P. Cancer immunogenicity, danger signals, and DAMPs: what, when, and how? BioFactors 2013; 39:355-67; PMID:; http://dx.doi.org/10.1002/biof.1125 PubMed DOI

Panaretakis T, Joza N, Modjtahedi N, Tesniere A, Vitale I, Durchschlag M, Fimia GM, Kepp O, Piacentini M, Froehlich KU, et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ 2008; 15:1499-509; PMID:; http://dx.doi.org/10.1038/cdd.2008.67 PubMed DOI

Kepp O, Gdoura A, Martins I, Panaretakis T, Schlemmer F, Tesniere A, Fimia GM, Ciccosanti F, Burgevin A, Piacentini M, et al. Lysyl tRNA synthetase is required for the translocation of calreticulin to the cell surface in immunogenic death. Cell Cycle 2010; 9:3072-7; PMID:; http://dx.doi.org/10.4161/cc.9.15.12459 PubMed DOI

Gardai SJ, Xiao YQ, Dickinson M, Nick JA, Voelker DR, Greene KE, Henson PM. By binding SIRPalpha or calreticulinCD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 2003; 115 13-23; PMID:; http://dx.doi.org/10.1016/S0092-8674(03)00758-X PubMed DOI

Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 2009; 15:1170-8; PMID:; http://dx.doi.org/10.1038/nm.2028 PubMed DOI

Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, Rubio N, Firczuk M, Mathieu C, Roebroek AJ, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J 2012; 31:1062-79; PMID:; http://dx.doi.org/10.1038/emboj.2011.497 PubMed DOI PMC

Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 2007; 109:4839-45; PMID:; http://dx.doi.org/10.1182/blood-2006-10-054221 PubMed DOI PMC

Tesniere A, Panaretakis T, Kepp O, Apetoh L, Ghiringhelli F, Zitvogel L, Kroemer G. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ 2008; 15:3-12; PMID:; http://dx.doi.org/10.1038/sj.cdd.4402269 PubMed DOI

Kepp O, Galluzzi L, Martins I, Schlemmer F, Adjemian S, Michaud M, Sukkurwala AQ, Menger L, Zitvogel L, Kroemer G. Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. Cancer Metast Rev 2011; 30:61-9; PMID:; http://dx.doi.org/10.1007/s10555-011-9273-4 PubMed DOI

Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011; 334:1573-7; PMID:; http://dx.doi.org/10.1126/science.1208347 PubMed DOI

Garg AD, Dudek AM, Agostinis P. Autophagy-dependent suppression of cancer immunogenicity and effector mechanisms of innate and adaptive immunity. Oncoimmunology 2013; 2:e26260; PMID:; http://dx.doi.org/10.4161/onci.26260 PubMed DOI PMC

Martins I, Tesniere A, Kepp O, Michaud M, Schlemmer F, Senovilla L, Séror C, Métivier D, Perfettini JL, Zitvogel L, et al. Chemotherapy induces ATP release from tumor cells. Cell Cycle 2009; 8:3723-8; PMID:; http://dx.doi.org/10.4161/cc.8.22.10026 PubMed DOI

Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 2012; 12:860-75; PMID:; http://dx.doi.org/10.1038/nrc3380 PubMed DOI

Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S, Kepp O, Métivier D, Galluzzi L, Perfettini JL, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ 2014; 21:79-91; PMID:; http://dx.doi.org/10.1038/cdd.2013.75 PubMed DOI PMC

Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418:191-5; PMID:; http://dx.doi.org/10.1038/nature00858 PubMed DOI

Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Ann Rev Immunol 2013; 31:51-72; PMID:; http://dx.doi.org/10.1146/annurev-immunol-032712-100008 PubMed DOI

Wesch D, Peters C, Oberg HH, Pietschmann K, Kabelitz D. Modulation of gammadelta T cell responses by TLR ligands. Cell Mol Life Sci: CMLS 2011; 68:2357-70; PMID:; http://dx.doi.org/10.1007/s00018-011-0699-1 PubMed DOI PMC

Dudek AM, Garg AD, Krysko DV, De Ruysscher D, Agostinis P. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev 2013; 24:319-33; PMID:; http://dx.doi.org/10.1016/j.cytogfr.2013.01.005 PubMed DOI

Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J, Spísek R. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res 2011; 71:4821-33; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-11-0950 PubMed DOI

Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, Aymeric L, Michaud M, Apetoh L, Barault L, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 2010; 29:482-91; PMID:; http://dx.doi.org/10.1038/onc.2009.356 PubMed DOI

Chen HM, Wang PH, Chen SS, Wen CC, Chen YH, Yang WC, Yang NS. Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol, Immunother: CII 2012; 61:1989-2002; PMID:; http://dx.doi.org/10.1007/s00262-012-1258-9 PubMed DOI PMC

Garrido G, Rabasa A, Sanchez B, Lopez MV, Blanco R, Lopez A, Hernández DR, Pérez R, Fernández LE. Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J Immunol 2011; 187:4954-66; PMID:; http://dx.doi.org/10.4049/jimmunol.1003477 PubMed DOI

Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F, Sanchez M, Lorenzi S, D'Urso MT, Belardelli F, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res 2011; 71:768-78; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-10-2788 PubMed DOI

Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S, Yamazaki T, Sukkurwala AQ, Michaud M, Mignot G, et al. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Translational Med 2012; 4:143ra99; PMID:; http://dx.doi.org/10.1126/scitranslmed.3003807 PubMed DOI

Abdul Qader Sukkurwala SA, Laura S, Mickaël M, Sabrina S, Erika V, Elisa Elena B, Lorenzo G, Laurence Z, Oliver K, Guido K. Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set. Oncoimmunology 2014; 3:e28473; PMID: PubMed PMC

Bugaut H, Bruchard M, Berger H, Derangere V, Odoul L, Euvrard R, Ladoire S, Chalmin F, Végran F, Rébé C, et al. Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells. PloS One 2013; 8:e65181; PMID:; http://dx.doi.org/10.1371/journal.pone.0065181 PubMed DOI PMC

Yang Y, Li XJ, Chen Z, Zhu XX, Wang J, Zhang LB, Qiang L, Ma YJ, Li ZY, Guo QL, et al. Wogonin induced calreticulinannexin A1 exposure dictates the immunogenicity of cancer cells in a PERKAKT dependent manner. PloS One 2012; 7:e50811; PMID:; http://dx.doi.org/10.1371/journal.pone.0050811 PubMed DOI PMC

West AC, Mattarollo SR, Shortt J, Cluse LA, Christiansen AJ, Smyth MJ, Johnstone RW. An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res 2013; 73:7265-76; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-13-0890 PubMed DOI

Weiss EM, Meister S, Janko C, Ebel N, Schlucker E, Meyer-Pittroff R, Fietkau R, Herrmann M, Gaipl US, Frey B. High hydrostatic pressure treatment generates inactivated mammalian tumor cells with immunogeneic features. J Immunotoxicol 2010; 7:194-204; PMID:; http://dx.doi.org/10.3109/15476911003657414 PubMed DOI

Fucikova J, Moserova I, Truxova I, Hermanova I, Vancurova I, Partlova S, Fialova A, Sojka L, Cartron PF, Houska M, et al. High hydrostatic pressure induces immunogenic cell death in human tumor cells. Int J Cancer J Int du Cancer 2014; 135:1165-77; PMID:; http://dx.doi.org/10.1002/ijc.28766 PubMed DOI

Garg AD, Krysko DV, Vandenabeele P, Agostinis P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol, Immunother: CII 2012; 61:215-21; PMID:; http://dx.doi.org/10.1007/s00262-011-1184-2 PubMed DOI PMC

Zamarin D, Holmgaard RB, Subudhi SK, Park JS, Mansour M, Palese P, Merghoub T, Wolchok JD, Allison JP. Localized ncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Translational Med 2014; 6:226ra32; PMID:; http://dx.doi.org/10.1126/scitranslmed.3008095 PubMed DOI PMC

Vacchelli E, Vitale I, Eggermont A, Fridman WH, Fucikova J, Cremer I, Galon J, Tartour E, Zitvogel L, Kroemer G, et al. . Trial watch: dendritic cell-based interventions for cancer therapy. Oncoimmunology 2013; 2:e25771; PMID:; http://dx.doi.org/10.4161/onci.25771 PubMed DOI PMC

Vacchelli E, Vitale I, Tartour E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: anticancer radioimmunotherapy. Oncoimmunology 2013; 2:e25595; PMID:; http://dx.doi.org/10.4161/onci.25595 PubMed DOI PMC

Golden EB, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC. The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2012; 2:88; PMID:; http://dx.doi.org/10.3389/fonc.2012.00088 PubMed DOI PMC

Rubner Y, Wunderlich R, Ruhle PF, Kulzer L, Werthmoller N, Frey B, Weiss EM, Keilholz L, Fietkau R, Gaipl US. How does ionizing irradiation contribute to the induction of anti-tumor immunity? Front Oncol 2012; 2:75; PMID:; http://dx.doi.org/10.3389/fonc.2012.00075 PubMed DOI PMC

Suzuki Y, Mimura K, Yoshimoto Y, Watanabe M, Ohkubo Y, Izawa S, Murata K, Fujii H, Nakano T, Kono K. Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res 2012; 72:3967-76; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-12-0851 PubMed DOI

Stangl S, Themelis G, Friedrich L, Ntziachristos V, Sarantopoulos A, Molls M, Skerra A, Multhoff G. Detection of irradiation-induced, membrane heat shock protein 70 (Hsp70) in mouse tumors using Hsp70 Fab fragment. Radiother Oncol: J Eur Soc Therap Radiol Oncol 2011; 99:313-6; PMID:; http://dx.doi.org/10.1016/j.radonc.2011.05.051 PubMed DOI

Brusa D, Migliore E, Garetto S, Simone M, Matera L. Immunogenicity of 56 degrees C and UVC-treated prostate cancer is associated with release of HSP70 and HMGB1 from necrotic cells. Prostate 2009; 69:1343-52; PMID:; http://dx.doi.org/10.1002/pros.20981 PubMed DOI

Prasad SJ, Farrand KJ, Matthews SA, Chang JH, McHugh RS, Ronchese F. Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells. J Immunol 2005; 174:90-8; PMID:; http://dx.doi.org/10.4049/jimmunol.174.1.90 PubMed DOI

Strome SE, Voss S, Wilcox R, Wakefield TL, Tamada K, Flies D, Chapoval A, Lu J, Kasperbauer JL, Padley D, et al. Strategies for antigen loading of dendritic cells to enhance the antitumor immune response. Cancer Res 2002; 62:1884-9; PMID: PubMed

Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol, Biol, Phys 2012; 83:1306-10; PMID:; http://dx.doi.org/10.1016/j.ijrobp.2011.09.049 PubMed DOI PMC

Carr-Brendel V, Markovic D, Smith M, Taylor-Papadimitriou J, Cohen EP. Immunity to breast cancer in mice immunized with X-irradiated breast cancer cells modified to secrete IL-12. J Immunother 1999; 22:415-22; PMID:; http://dx.doi.org/10.1097/00002371-199909000-00005 PubMed DOI

Kachikwu EL, Iwamoto KS, Liao YP, DeMarco JJ, Agazaryan N, Economou JS, McBride WH, Schaue D. Radiation enhances regulatory T cell representation. Int J Radiat Oncol, Biol, Phys 2011; 81:1128-35; PMID:; http://dx.doi.org/10.1016/j.ijrobp.2010.09.034 PubMed DOI PMC

Baba J, Watanabe S, Saida Y, Tanaka T, Miyabayashi T, Koshio J, Ichikawa K, Nozaki K, Koya T, Deguchi K, et al. Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia. Blood 2012; 120:2417-27; PMID:; http://dx.doi.org/10.1182/blood-2012-02-411124 PubMed DOI

Gorin JB, Menager J, Gouard S, Maurel C, Guilloux Y, Faivre-Chauvet A, Morgenstern A, Bruchertseifer F, Chérel M, Davodeau F, et al. Antitumor immunity induced after alpha irradiation. Neoplasia 2014; 16:319-28; PMID:; http://dx.doi.org/10.1016/j.neo.2014.04.002 PubMed DOI PMC

Frey B, Stache C, Rubner Y, Werthmoller N, Schulz K, Sieber R, Semrau S, Rödel F, Fietkau R, Gaipl US. Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential. J Immunotoxicol 2012; 9:301-13; PMID:; http://dx.doi.org/10.3109/1547691X.2012.693547 PubMed DOI

Frey B, Rubner Y, Kulzer L, Werthmoller N, Weiss EM, Fietkau R, Gaipl US. Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol, Immunother: CII 2014; 63:29-36; PMID:; http://dx.doi.org/10.1007/s00262-013-1474-y PubMed DOI PMC

Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Nat Cancer Inst 2013; 105:256-65; PMID:; http://dx.doi.org/10.1093/jnci/djs629 PubMed DOI PMC

Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. New Engl J Med 2012; 366:925-31; PMID:; http://dx.doi.org/10.1056/NEJMoa1112824 PubMed DOI PMC

Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. New Engl J Med 2010; 363:411-22; PMID:; http://dx.doi.org/10.1056/NEJMoa1001294 PubMed DOI

Maverakis E, Miyamura Y, Bowen MP, Correa G, Ono Y, Goodarzi H. Light, including ultraviolet. J Autoimmun 2010; 34:J247-57; PMID:; http://dx.doi.org/10.1016/j.jaut.2009.11.011 PubMed DOI PMC

Widel M, Krzywon A, Gajda K, Skonieczna M, Rzeszowska-Wolny J. Induction of bystander effects by UVA, UVB, and UVC radiation in human fibroblasts and the implication of reactive oxygen species. Free Radical Biol Med 2014; 68:278-87; PMID:; http://dx.doi.org/10.1016/j.freeradbiomed.2013.12.021 PubMed DOI

Zhong JL, Yang L, Lu F, Xiao H, Xu R, Wang L, Zhu F, Zhang Y. UVA, UVB and UVC induce differential response signaling pathways converged on the eIF2alpha phosphorylation. Photochem Photobiol 2011; 87:1092-104; PMID:; http://dx.doi.org/10.1111/j.1751-1097.2011.00963.x PubMed DOI

Anand S, Chakrabarti E, Kawamura H, Taylor CR, Maytin EV. Ultraviolet light (UVB and UVA) induces the damage-responsive transcription factor CHOPgadd153 in murine and human epidermis: evidence for a mechanism specific to intact skin. J Invest Dermatol 2005; 125 323-33; PMID: PubMed

Eaglstein WH, Sakai M, Mizuno N. Ultraviolet radiation-induced inflammation and leukocytes. J Invest Dermatol 1979; 72:59-63; PMID:; http://dx.doi.org/10.1111/1523-1747.ep12530248 PubMed DOI

Begovic M, Herberman RB, Gorelik E. Ultraviolet light-induced increase in tumor cell susceptibility to TNF-dependent and TNF-independent natural cell-mediated cytotoxicity. Cell Immunol 1991; 138:349-59; PMID:; http://dx.doi.org/10.1016/0008-8749(91)90159-9 PubMed DOI

Momiyama M, Suetsugu A, Kimura H, Kishimoto H, Aki R, Yamada A, Sakurada H, Chishima T, Bouvet M, Endo I, et al. Imaging the efficacy of UVC irradiation on superficial brain tumors and metastasis in live mice at the subcellular level. J Cell Biochem 2013; 114:428-34; PMID:; http://dx.doi.org/10.1002/jcb.24381 PubMed DOI

Frey B, Franz S, Sheriff A, Korn A, Bluemelhuber G, Gaipl US, Voll RE, Meyer-Pittroff R, Herrmann M. Hydrostatic pressure induced death of mammalian cells engages pathways related to apoptosis or necrosis. Cell Mol Biol (Noisy-Le-Grand) 2004; 50:459-67; PMID: PubMed

Korn A, Frey B, Sheriff A, Gaipl US, Franz S, Meyer-Pittroff R, Bluemelhuberh G, Herrmann M. High hydrostatic pressure inactivated human tumour cells preserve their immunogenicity. Cell Mol Biol (Noisy-Le-Grand) 2004; 50:469-77; PMID: PubMed

Frey B, Janko C, Ebel N, Meister S, Schlucker E, Meyer-Pittroff R, Fietkau R, Herrmann M, Gaipl US. Cells under pressure - treatment of eukaryotic cells with high hydrostatic pressure, from physiologic aspects to pressure induced cell death. Curr Med Chem 2008; 15:2329-36; PMID:; http://dx.doi.org/10.2174/092986708785909166 PubMed DOI

Diehl P, Schauwecker J, Mittelmeier W, Schmitt M. High hydrostatic pressure, a novel approach in orthopedic surgical oncology to disinfect bone, tendons and cartilage. Anticancer Res 2008; 28:3877-83; PMID: PubMed

Helmstein K. Treatment of bladder carcinoma by a hydrostatic pressure technique. Report on 43 cases. Brit J Urol 1972; 44:434-50; PMID:; http://dx.doi.org/10.1111/j.1464-410X.1972.tb10103.x PubMed DOI

Coombes GB. A clinical evaluation of hydrostatic pressure treatment for carcinoma of the bladder. Brit J Urol 1975; 47:177-83; PMID:; http://dx.doi.org/10.1111/j.1464-410X.1975.tb03943.x PubMed DOI

Eisenthal A, Ramakrishna V, Skornick Y, Shinitzky M. Induction of cell-mediated immunity against B16-BL6 melanoma in mice vaccinated with cells modified by hydrostatic pressure and chemical crosslinking. Cancer Immunol, Immunother: CII 1993; 36:300-6; PMID:; http://dx.doi.org/10.1007/BF01741168 PubMed DOI PMC

Goldman Y, Peled A, Shinitzky M. Effective elimination of lung metastases induced by tumor cells treated with hydrostatic pressure and N-acetyl-L-cysteine. Cancer Res 2000; 60:350-8; PMID: PubMed

Eisenthal A, Goldman Y, Skornick Y, Gelfand A, Buyaner D, Kaver I, Yellin A, Yehoshua H, Lifschitz-Mercer B, Gonnene A, et al. Human tumor cells, modified by a novel pressurecrosslinking methodology, promote autologous lymphocyte proliferation and modulate cytokine secretion. Cancer Immunol, Immunother: CII 1998; 46:304-10; PMID:; http://dx.doi.org/10.1007/s002620050491 PubMed DOI PMC

Shinitzky M, Goldman Y. Immunotherapy of cancer with pressure modified cells. Isr Med Assoc J 2000; 2:615-20; PMID: PubMed

Fucikova J, Moserova I, Truxova I, Hermanova I, Vancurova I, Partlova S, Sojka L, Cartron PF, Houska M, Rob L, et al. Article title: high hydrostatic pressure induces immunogenic cell death in human tumor cells. Int J Cancer 2014; 135:1165-77; PMID:; http://dx.doi.org/10.1002/ijc.28766 PubMed DOI

Rozkova D, Tiserova H, Fucikova J, Last’ovicka J, Podrazil M, Ulcova H, Budínský V, Prausová J, Linke Z, Minárik I, et al. FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer. Clinical Immunol 2009; 131:1-10; PMID:; http://dx.doi.org/10.1016/j.clim.2009.01.001 PubMed DOI

Garg AD, Agostinis P. ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. Photochem Photobiol Sci: Off J Eur Photochem Assoc Euro Soc Photobiol 2014; 13:474-87; PMID:; http://dx.doi.org/10.1039/c3pp50333j PubMed DOI

Garg AD, Nowis D, Golab J, Agostinis P. Photodynamic therapy: illuminating the road from cell death towards anti-tumour immunity. Apoptosis 2010; 15:1050-71; PMID:; http://dx.doi.org/10.1007/s10495-010-0479-7 PubMed DOI

Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, Hahn SM, Hamblin MR, Juzeniene A, Kessel D, et al. Photodynamic therapy of cancer: an update. CA Cancer J Clin 2011; 61:250-81; PMID:; http://dx.doi.org/10.3322/caac.20114 PubMed DOI PMC

Buytaert E, Dewaele M, Agostinis P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochimica et Biophysica Acta 2007; 1776:86-107; PMID: PubMed

Kabingu E, Oseroff AR, Wilding GE, Gollnick SO. Enhanced systemic immune reactivity to a Basal cell carcinoma associated antigen following photodynamic therapy. Clin Cancer Res: Off J Am Assoc Cancer Res 2009; 15:4460-6; PMID:; http://dx.doi.org/10.1158/1078-0432.CCR-09-0400 PubMed DOI PMC

Thong PS, Ong KW, Goh NS, Kho KW, Manivasager V, Bhuvaneswari R, Olivo M, Soo KC. Photodynamic-therapy-activated immune response against distant untreated tumours in recurrent angiosarcoma. Lancet Oncol 2007; 8:950-2; PMID:; http://dx.doi.org/10.1016/S1470-2045(07)70318-2 PubMed DOI

Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, Piette J, Linehan C, Gupta S, Samali A, et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ 2012; 19:1880-91; PMID:; http://dx.doi.org/10.1038/cdd.2012.74 PubMed DOI PMC

Verfaillie T, van Vliet A, Garg AD, Dewaele M, Rubio N, Gupta S, de Witte P, Samali A, Agostinis P. Pro-apoptotic signaling induced by photo-oxidative ER stress is amplified by Noxa, not Bim. Biochem Biophys Res Commun 2013; 438:500-6; PMID:; http://dx.doi.org/10.1016/j.bbrc.2013.07.107 PubMed DOI

Kacerovska D, Pizinger K, Majer F, Smid F. Photodynamic therapy of nonmelanoma skin cancer with topical hypericum perforatum extract+a pilot study. Photochem Photobiol 2008; 84:779-85; PMID:; http://dx.doi.org/10.1111/j.1751-1097.2007.00260.x PubMed DOI

Rook AH, Wood GS, Duvic M, Vonderheid EC, Tobia A, Cabana B. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J Am Acad Dermatol 2010; 63:984-90; PMID:; http://dx.doi.org/10.1016/j.jaad.2010.02.039 PubMed DOI

Koren H, Schenk GM, Jindra RH, Alth G, Ebermann R, Kubin A, Koderhold G, Kreitner M. Hypericin in phototherapy. J Photochem Photobiol B, Biol 1996; 36:113-9; PMID:; http://dx.doi.org/10.1016/S1011-1344(96)07357-5 PubMed DOI

Alecu M, Ursaciuc C, Halalau F, Coman G, Merlevede W, Waelkens E, de Witte P. Photodynamic treatment of basal cell carcinoma and squamous cell carcinoma with hypericin. Anticancer Res 1998; 18:4651-4; PMID: PubMed

Garg AD, Dudek AM, Agostinis P. Calreticulin surface exposure is abrogated in cells lacking, chaperone-mediated autophagy-essential gene, LAMP2A. Cell Death Dis 2013; 4:e826; PMID:; http://dx.doi.org/10.1038/cddis.2013.372 PubMed DOI PMC

Garg AD, Dudek AM, Ferreira GB, Verfaillie T, Vandenabeele P, Krysko DV, Mathieu C, Agostinis P. ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy 2013; 9:1292-307; PMID:; http://dx.doi.org/10.4161/auto.25399 PubMed DOI

Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002; 62:1604-8; PMID: PubMed

Zhang H, Ma W, Li Y. Generation of effective vaccines against liver cancer by using photodynamic therapy. Lasers Med Sci 2009; 24:549-52; PMID:; http://dx.doi.org/10.1007/s10103-008-0609-4 PubMed DOI

Korbelik M, Sun J. Photodynamic therapy-generated vaccine for cancer therapy. Cancer Immunol, Immunother: CII 2006; 55:900-9; PMID:; http://dx.doi.org/10.1007/s00262-005-0088-4 PubMed DOI PMC

Jalili A, Makowski M, Switaj T, Nowis D, Wilczynski GM, Wilczek E, Chorazy-Massalska M, Radzikowska A, Maslinski W, Biały L, et al. Effective photoimmunotherapy of murine colon carcinoma induced by the combination of photodynamic therapy and dendritic cells. Clin Cancer Res: Off J Am Assoc Cancer Res 2004; 10:4498-508; PMID:; http://dx.doi.org/10.1158/1078-0432.CCR-04-0367 PubMed DOI

Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 2002; 43:33-56; PMID:; http://dx.doi.org/10.1016/S1040-8428(01)00179-2 PubMed DOI

Harmon BV, Corder AM, Collins RJ, Gobe GC, Allen J, Allan DJ, Kerr JF. Cell death induced in a murine mastocytoma by 42-47 degrees C heating in vitro: evidence that the form of death changes from apoptosis to necrosis above a critical heat load. Int J Radiat Biol 1990; 58:845-58; PMID:; http://dx.doi.org/10.1080/09553009014552221 PubMed DOI

Feng H, Zeng Y, Graner MW, Likhacheva A, Katsanis E. Exogenous stress proteins enhance the immunogenicity of apoptotic tumor cells and stimulate antitumor immunity. Blood 2003; 101:245-52; PMID:; http://dx.doi.org/10.1182/blood-2002-05-1580 PubMed DOI

Shi H, Cao T, Connolly JE, Monnet L, Bennett L, Chapel S, Bagnis C, Mannoni P, Davoust J, Palucka AK, et al. Hyperthermia enhances CTL cross-priming. J Immunol 2006; 176:2134-41; PMID:; http://dx.doi.org/10.4049/jimmunol.176.4.2134 PubMed DOI

Masse D, Ebstein F, Bougras G, Harb J, Meflah K, Gregoire M. Increased expression of inducible HSP70 in apoptotic cells is correlated with their efficacy for antitumor vaccine therapy. Int J Cancer J Int du Cancer 2004; 111:575-83; PMID:; http://dx.doi.org/10.1002/ijc.20249 PubMed DOI

Gordon RT, Hines JR, Gordon D. Intracellular hyperthermia. A biophysical approach to cancer treatment via intracellular temperature and biophysical alterations. Med Hypotheses 1979; 5:83-102; PMID:; http://dx.doi.org/10.1016/0306-9877(79)90063-X PubMed DOI

Ito A, Shinkai M, Honda H, Yoshikawa K, Saga S, Wakabayashi T, Yoshida J, Kobayashi T. Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol, Immunother: CII 2003; 52:80-8; PMID: PubMed PMC

Ito A, Honda H, Kobayashi T. Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: a novel concept of “heat-controlled necrosis” with heat shock protein expression. Cancer Immunol, Immunother: CII 2006; 55:320-8; PMID:; http://dx.doi.org/10.1007/s00262-005-0049-y PubMed DOI PMC

Wang H, Zhang L, Shi Y, Javidiparsijani S, Wang G, Li X, Ouyang W, Zhou J, Zhao L, Wang X, et al. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats. Oncol Lett 2014; 7:764-70; PMID: PubMed PMC

Xu X, Gupta S, Hu W, McGrath BC, Cavener DR. Hyperthermia induces the ER stress pathway. PloS One 2011; 6:e23740; PMID:; http://dx.doi.org/10.1371/journal.pone.0023740 PubMed DOI PMC

Chen T, Guo J, Han C, Yang M, Cao X. Heat shock protein 70, released from heat-stressed tumor cells, initiates antitumor immunity by inducing tumor cell chemokine production and activating dendritic cells via TLR4 pathway. J Immunol 2009; 182:1449-59; PMID:; http://dx.doi.org/10.4049/jimmunol.182.3.1449 PubMed DOI

Frey B, Weiss EM, Rubner Y, Wunderlich R, Ott OJ, Sauer R, Fietkau R, Gaipl US. Old and new facts about hyperthermia-induced modulations of the immune system. Int J Hyperther: Off J Eur Soc Hyperther Oncol, N Am Hyperther Group 2012; 28:528-42; PMID:; http://dx.doi.org/10.3109/02656736.2012.677933 PubMed DOI

Weiss EM, Frey B, Rodel F, Herrmann M, Schlucker E, Voll RE, Fietkau R, Gaipl US. Ex vivo- and in vivo-induced dead tumor cells as modulators of antitumor responses. Ann New York Acad Sci 2010; 1209:109-17; PMID:; http://dx.doi.org/10.1111/j.1749-6632.2010.05743.x PubMed DOI

Mantel F, Frey B, Haslinger S, Schildkopf P, Sieber R, Ott OJ, Lödermann B, Rödel F, Sauer R, Fietkau R, et al. Combination of ionising irradiation and hyperthermia activates programmed apoptotic and necrotic cell death pathways in human colorectal carcinoma cells. Strahlenther Onkol 2010; 186:587-99; PMID:; http://dx.doi.org/10.1007/s00066-010-2154-x PubMed DOI

Schildkopf P, Frey B, Ott OJ, Rubner Y, Multhoff G, Sauer R, Fietkau R, Gaipl US. Radiation combined with hyperthermia induces HSP70-dependent maturation of dendritic cells and release of pro-inflammatory cytokines by dendritic cells and macrophages. Radiother Oncol: J Eur Soc Therap Radiol Oncol 2011; 101:109-15; PMID:; http://dx.doi.org/10.1016/j.radonc.2011.05.056 PubMed DOI

Qin Y, Lu J, Bao L, Zhu H, Li J, Li L, Jiang B, Huang X. Bortezomib improves progression-free survival in multiple myeloma patients overexpressing preferentially expressed antigen of melanoma. Chinese Med J 2014; 127:1666-71; PMID: PubMed

Audia S, Nicolas A, Cathelin D, Larmonier N, Ferrand C, Foucher P, Fanton A, Bergoin E, Maynadie M, Arnould L, et al. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+ T lymphocytes. Clin Exp Immunol 2007; 150:523-30; PMID:; http://dx.doi.org/10.1111/j.1365-2249.2007.03521.x PubMed DOI PMC

Viaud S, Flament C, Zoubir M, Pautier P, LeCesne A, Ribrag V, Soria JC, Marty V, Vielh P, Robert C, et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res 2011; 71:661-5; PMID:; http://dx.doi.org/10.1158/0008-5472.CAN-10-1259 PubMed DOI

Calreticulin and cancer

Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications

Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death

Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure inhibit prostate tumor growth in TRAMP mice

Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells

Generation of dendritic cell-based vaccine using high hydrostatic pressure for non-small cell lung cancer immunotherapy

Generation of T cell effectors using tumor cell-loaded dendritic cells for adoptive T cell therapy

Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy

Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure induce strong immune responses and display therapeutic effects both in murine TC-1 and TRAMP-C2 tumors when combined with docetaxel chemotherapy

Trial Watch-Oncolytic viruses and cancer therapy

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death