CoChat
Sign Up
Cited by 1,138Immunotherapy and Immune ResponsesCell death mechanisms and regulationCancer Immunotherapy and Biomarkers

Detection of immunogenic cell death and its relevance for cancer therapy

Open access
Fucikova, Jitka, Kepp, Oliver, Kasikova, Lenka, Petroni, Giulia, Yamazaki, Takahiro, Liu, Peng, Zhao, Liwei, Spisek, Radek +2 more·2020·Cell Death & Disease
DOI 10.1038/s41419-020-03221-2PMC PMC7691519
Open this paper in CoChat — free accountOpen PDF

Abstract

Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41419-020-03221-2

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The low response to immunotherapy in breast cancer may be related to the immunosuppressive tumor microenvironment.

    “These findings may be related to the immunosuppressive TME of breast cancer [86, 87].”

    From Nanosensitizer-assisted sonodynamic therapy for breast cancer (2025) · cites this paper as [86]

    The Introduction (page unavailable) explains that tumors can evade immune responses and that some become resistant to checkpoint immunotherapy. The ATP section (page unavailable) describes immunosuppressive effects in malignant tissue, but it does not connect an immunosuppressive microenvironment to low immunotherapy response specifically in breast cancer. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 183

  1. [1]Smyth MJ Dunn GP Schreiber RD Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity Adv. Immunol. 2006 90 1 50 10.1016/S0065-2776(06)90001-7 16730260 · DOI
  2. [2]Schreiber RD Old LJ Smyth MJ Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion Science 2011 331 1565 1570 10.1126/science.1203486 21436444 · DOI · Paper page
  3. [3]Galluzzi L Spranger S Fuchs E López-Soto A WNT signaling in cancer immunosurveillance Trends Cell Biol. 2019 29 44 65 10.1016/j.tcb.2018.08.005 30220580 PMC7001864 · DOI
  4. [4]Salmon H Remark R Gnjatic S Merad M Host tissue determinants of tumour immunity Nat. Rev. Cancer 2019 19 215 227 30867580 PMC7787168
  5. [6]Galon J Angell HK Bedognetti D Marincola FM The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures Immunity 2013 39 11 26 10.1016/j.immuni.2013.07.008 23890060 · DOI
  6. [7]Roumenina LT Daugan MV Petitprez F Sautes-Fridman C Fridman WH Context-dependent roles of complement in cancer Nat. Rev. Cancer 2019 19 698 715 10.1038/s41568-019-0210-0 31666715 · DOI
  7. [8]Chalmin F Humblin E Ghiringhelli F Vegran F Transcriptional programs underlying Cd4 T cell differentiation and functions Int. Rev. Cell Mol. Biol. 2018 341 1 61 10.1016/bs.ircmb.2018.07.002 30262030 · DOI
  8. [9]Peng D Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy Nature 2015 527 249 253 10.1038/nature15520 26503055 PMC4779053 · DOI · Paper page
  9. [10]Dunn GP Koebel CM Schreiber RD Interferons, immunity and cancer immunoediting Nat. Rev. Immunol. 2006 6 836 848 10.1038/nri1961 17063185 · DOI · Paper page
  10. [11]Rao S Gharib K Han A Cancer immunosurveillance by T cells Int Rev. Cell Mol. Biol. 2019 342 149 173 10.1016/bs.ircmb.2018.08.001 30635090 · DOI
  11. [12]Dunn GP Old LJ Schreiber RD The immunobiology of cancer immunosurveillance and immunoediting Immunity 2004 21 137 148 10.1016/j.immuni.2004.07.017 15308095 · DOI
  12. [13]Ivashkiv LB IFNgamma: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy Nat. Rev. Immunol. 2018 18 545 558 10.1038/s41577-018-0029-z 29921905 PMC6340644 · DOI
  13. [15]Haen SP Loffler MW Rammensee HG Brossart P Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire Nat. Rev. Clin. Oncol. 2020 17 595 610 10.1038/s41571-020-0387-x 32572208 PMC7306938 · DOI
  14. [16]Galluzzi L Consensus guidelines for the definition, detection and interpretation of immunogenic cell death J. Immunother. Cancer 2020 8 e000337 10.1136/jitc-2019-000337 32209603 PMC7064135 · DOI
  15. [17]Smith CC Alternative tumour-specific antigens Nat. Rev. Cancer 2019 19 465 478 10.1038/s41568-019-0162-4 31278396 PMC6874891 · DOI
  16. [18]Vitale I Mutational and antigenic landscape in tumor progression and cancer immunotherapy Trends Cell Biol. 2019 29 396 416 10.1016/j.tcb.2019.01.003 30765144 · DOI
  17. [19]Hu Z Ott PA Wu CJ Towards personalized, tumour-specific, therapeutic vaccines for cancer Nat. Rev. Immunol. 2018 18 168 182 10.1038/nri.2017.131 29226910 PMC6508552 · DOI · Paper page
  18. [20]Ren Y HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer Oncoimmunology 2020 9 1744947 10.1080/2162402X.2020.1744947 32523802 PMC7255108 · DOI
  19. [22]Kotsias F Cebrian I Alloatti A Antigen processing and presentation Int. Rev. Cell Mol. Biol. 2019 348 69 121 10.1016/bs.ircmb.2019.07.005 31810556 · DOI · Paper page
  20. [23]Yamamoto K Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I Nature 2020 581 100 105 10.1038/s41586-020-2229-5 32376951 PMC7296553 · DOI · Paper page
  21. [24]Kalbasi A Ribas A Tumour-intrinsic resistance to immune checkpoint blockade Nat. Rev. Immunol. 2020 20 25 39 10.1038/s41577-019-0218-4 31570880 PMC8499690 · DOI
  22. [25]Lee JH Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition Nat. Commun. 2020 11 1897 10.1038/s41467-020-15726-7 32312968 PMC7171183 · DOI
  23. [26]Lee YS Radford KJ The role of dendritic cells in cancer Int. Rev. Cell Mol. Biol. 2019 348 123 178 10.1016/bs.ircmb.2019.07.006 31810552 · DOI
  24. [27]Martinek J Wu TC Cadena D Banchereau J Palucka K Interplay between dendritic cells and cancer cells Int. Rev. Cell Mol. Biol. 2019 348 179 215 10.1016/bs.ircmb.2019.07.008 31810553 · DOI
  25. [28]Vacchelli E Trial watch: dendritic cell-based interventions for cancer therapy Oncoimmunology 2013 2 e25771 10.4161/onci.25771 24286020 PMC3841205 · DOI
  26. [29]Worbs T Hammerschmidt SI Forster R Dendritic cell migration in health and disease Nat. Rev. Immunol. 2017 17 30 48 10.1038/nri.2016.116 27890914 · DOI
  27. [30]Amon L Transcriptional control of dendritic cell development and functions Int. Rev. Cell Mol. Biol. 2019 349 55 151 10.1016/bs.ircmb.2019.10.001 31759434 · DOI
  28. [31]Krysko O Løve Aaes T Bachert C Vandenabeele P Krysko DV Many faces of DAMPs in cancer therapy Cell Death Dis. 2013 4 e631 10.1038/cddis.2013.156 23681226 PMC3674363 · DOI
  29. [33]Balan S Saxena M Bhardwaj N Dendritic cell subsets and locations Int. Rev. Cell Mol. Biol. 2019 348 1 68 10.1016/bs.ircmb.2019.07.004 31810551 · DOI
  30. [34]Gong T Liu L Jiang W Zhou R DAMP-sensing receptors in sterile inflammation and inflammatory diseases Nat. Rev. Immunol. 2020 20 95 112 10.1038/s41577-019-0215-7 31558839 · DOI · Paper page
  31. [35]Bloes DA Kretschmer D Peschel A Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors Nat. Rev. Microbiol. 2015 13 95 104 10.1038/nrmicro3390 25534805 · DOI
  32. [37]Yatim N Cullen S Albert ML Dying cells actively regulate adaptive immune responses Nat. Rev. Immunol. 2017 17 262 275 10.1038/nri.2017.9 28287107 · DOI · Paper page
  33. [38]Krysko DV Immunogenic cell death and DAMPs in cancer therapy Nat. Rev. Cancer 2012 12 860 875 10.1038/nrc3380 23151605 · DOI · Paper page
  34. [39]Zhou J Immunogenic cell death in cancer therapy: present and emerging inducers J. Cell Mol. Med. 2019 23 4854 4865 10.1111/jcmm.14356 31210425 PMC6653385 · DOI
  35. [40]Garg AD Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation Biochim. Biophys. Acta 2010 1805 53 71 19720113
  36. [41]Boada-Romero E Martinez J Heckmann BL Green DR The clearance of dead cells by efferocytosis Nat. Rev. Mol. Cell Biol. 2020 21 398 414 10.1038/s41580-020-0232-1 32251387 PMC7392086 · DOI
  37. [42]Paludan SR Reinert LS Hornung V DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer Nat. Rev. Immunol. 2019 19 141 153 10.1038/s41577-018-0117-0 30644449 PMC7311199 · DOI
  38. [43]Vanpouille-Box C Hoffmann JA Galluzzi L Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles Nat. Rev. Drug Discov. 2019 18 845 867 10.1038/s41573-019-0043-2 31554927 · DOI · Paper page
  39. [45]Fucikova J Prognostic and predictive value of DAMPs and DAMP-associated processes in cancer Front. Immunol. 2015 6 402 10.3389/fimmu.2015.00402 26300886 PMC4528281 · DOI · Paper page
  40. [46]Galluzzi L Humeau J Buque A Zitvogel L Kroemer G Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors Nat. Rev. Clin. Oncol. 2020 17 725 741 10.1038/s41571-020-0413-z 32760014 · DOI · Paper page
  41. [47]Deutsch E Chargari C Galluzzi L Kroemer G Optimising efficacy and reducing toxicity of anticancer radioimmunotherapy Lancet Oncol. 2019 20 e452 e463 10.1016/S1470-2045(19)30171-8 31364597 · DOI
  42. [48]Ye W ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer Oncoimmunology 2020 9 1710398 10.1080/2162402X.2019.1710398 32002309 PMC6959437 · DOI
  43. [49]Xiao R Antagonist of cIAP1/2 and XIAP enhances anti-tumor immunity when combined with radiation and PD-1 blockade in a syngeneic model of head and neck cancer Oncoimmunology 2018 7 e1471440 10.1080/2162402X.2018.1471440 30393585 PMC6209421 · DOI
  44. [50]Pol J Trial Watch: immunogenic cell death inducers for anticancer chemotherapy Oncoimmunology 2015 4 e1008866 10.1080/2162402X.2015.1008866 26137404 PMC4485780 · DOI
  45. [51]Hwang WL Pike LRG Royce TJ Mahal BA Loeffler JS Safety of combining radiotherapy with immune-checkpoint inhibition Nat. Rev. Clin. Oncol. 2018 15 477 494 10.1038/s41571-018-0046-7 29872177 · DOI
  46. [52]Galon J Bruni D Approaches to treat immune hot, altered and cold tumours with combination immunotherapies Nat. Rev. Drug Discov. 2019 18 197 218 10.1038/s41573-018-0007-y 30610226 · DOI
  47. [53]Ngwa W Using immunotherapy to boost the abscopal effect Nat. Rev. Cancer 2018 18 313 322 10.1038/nrc.2018.6 29449659 PMC5912991 · DOI · Paper page
  48. [54]Truxova I Rationale for the combination of dendritic cell-based vaccination approaches with chemotherapy agents Int. Rev. Cell Mol. Biol. 2017 330 115 156 10.1016/bs.ircmb.2016.09.003 28215530 · DOI
  49. [55]Brown JS Sundar R Lopez J Combining DNA damaging therapeutics with immunotherapy: more haste, less speed Br. J. Cancer 2018 118 312 324 10.1038/bjc.2017.376 29123260 PMC5808021 · DOI
  50. [57]Voorwerk L Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial Nat. Med. 2019 25 920 928 10.1038/s41591-019-0432-4 31086347 · DOI
  51. [58]Yamazaki T Buqué A Ames TD Galluzzi L PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models Oncoimmunology 2020 9 1721810 10.1080/2162402X.2020.1721810 32117585 PMC7028345 · DOI
  52. [60]D’Amico L A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer J. Immunother. Cancer 2019 7 16 10.1186/s40425-018-0464-1 30665463 PMC6341578 · DOI
  53. [61]Vacchelli E Trial Watch: chemotherapy with immunogenic cell death inducers Oncoimmunology 2014 3 e27878 10.4161/onci.27878 24800173 PMC4008470 · DOI
  54. [62]Han X Vesely MD Stimulating T cells against cancer with agonist immunostimulatory monoclonal antibodies Int. Rev. Cell Mol. Biol. 2019 342 1 25 10.1016/bs.ircmb.2018.07.003 30635089 PMC6487201 · DOI
  55. [64]Aranda F Trial Watch: immunostimulatory monoclonal antibodies in cancer therapy Oncoimmunology 2014 3 e27297 10.4161/onci.27297 24701370 PMC3961485 · DOI
  56. [65]Borrie AE Maleki Vareki S T lymphocyte-based cancer immunotherapeutics Int. Rev. Cell Mol. Biol. 2018 341 201 276 10.1016/bs.ircmb.2018.05.010 30262033 · DOI
  57. [66]Sun C Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B Immunol. Lett. 2015 164 65 71 10.1016/j.imlet.2015.02.007 25721381 · DOI
  58. [67]Donnelly OG Measles virus causes immunogenic cell death in human melanoma Gene Ther. 2013 20 7 15 10.1038/gt.2011.205 22170342 PMC3378495 · DOI
  59. [69]Dudek AM Garg AD Krysko DV De Ruysscher D Agostinis P Inducers of immunogenic cancer cell death Cytokine Growth Factor Rev. 2013 24 319 333 10.1016/j.cytogfr.2013.01.005 23391812 · DOI
  60. [70]Serrano-Del Valle A Anel A Naval J Marzo I Immunogenic cell death and immunotherapy of multiple myeloma Front. Cell Dev. Biol. 2019 7 50 10.3389/fcell.2019.00050 31041312 PMC6476910 · DOI
  61. [71]Giglio P PKR and GCN2 stress kinases promote an ER stress-independent eIF2alpha phosphorylation responsible for calreticulin exposure in melanoma cells Oncoimmunology 2018 7 e1466765 10.1080/2162402X.2018.1466765 30221067 PMC6136861 · DOI
  62. [72]Huang FY Induction of enhanced immunogenic cell death through ultrasound-controlled release of doxorubicin by liposome-microbubble complexes Oncoimmunology 2018 7 e1446720 10.1080/2162402X.2018.1446720 29900064 PMC5993503 · DOI
  63. [75]Chabanon RM PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer J. Clin. Invest. 2019 129 1211 1228 10.1172/JCI123319 30589644 PMC6391116 · DOI · Paper page
  64. [79]Tatsuno K Extracorporeal photochemotherapy induces bona fide immunogenic cell death Cell Death Dis. 2019 10 578 10.1038/s41419-019-1819-3 31371700 PMC6675789 · DOI
  65. [80]Fucikova J High hydrostatic pressure induces immunogenic cell death in human tumor cells Int. J. Cancer 2014 135 1165 1177 10.1002/ijc.28766 24500981 · DOI
  66. [81]Krombach J Priming anti-tumor immunity by radiotherapy: dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells Oncoimmunology 2019 8 e1523097 10.1080/2162402X.2018.1523097 30546963 PMC6287777 · DOI
  67. [82]Di Virgilio F Sarti AC Falzoni S De Marchi E Adinolfi E Extracellular ATP and P2 purinergic signalling in the tumour microenvironment Nat. Rev. Cancer 2018 18 601 618 10.1038/s41568-018-0037-0 30006588 · DOI
  68. [85]Humeau J Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress EMBO Mol. Med. 2020 12 e11622 10.15252/emmm.201911622 32323922 PMC7207166 · DOI
  69. [86]Michaud M Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice Science 2011 334 1573 1577 10.1126/science.1208347 22174255 · DOI · Paper page
  70. [87]Bezu L eIF2α phosphorylation: a hallmark of immunogenic cell death Oncoimmunology 2018 7 e1431089 10.1080/2162402X.2018.1431089 29872560 PMC5980344 · DOI
  71. [88]Rybstein MD Bravo-San Pedro JM Kroemer G Galluzzi L The autophagic network and cancer Nat. Cell Biol. 2018 20 243 251 10.1038/s41556-018-0042-2 29476153 · DOI
  72. [91]Kasikova L Calreticulin exposure correlates with robust adaptive antitumor immunity and favorable prognosis in ovarian carcinoma patients J. Immunother. Cancer 2019 7 312 10.1186/s40425-019-0781-z 31747968 PMC6868694 · DOI · Paper page
  73. [92]Guermonprez P Gerber-Ferder Y Vaivode K Bourdely P Helft J Origin and development of classical dendritic cells Int. Rev. Cell Mol. Biol. 2019 349 1 54 10.1016/bs.ircmb.2019.08.002 31759429 · DOI
  74. [93]Schcolnik-Cabrera A Calreticulin in phagocytosis and cancer: opposite roles in immune response outcomes Apoptosis 2019 24 245 255 10.1007/s10495-019-01532-0 30929105 · DOI
  75. [95]Gardai SJ Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte Cell 2005 123 321 334 10.1016/j.cell.2005.08.032 16239148 · DOI · Paper page
  76. [96]Gardai SJ By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation Cell 2003 115 13 23 10.1016/S0092-8674(03)00758-X 14531999 · DOI
  77. [97]Byrne JC Bruton’s tyrosine kinase is required for apoptotic cell uptake via regulating the phosphorylation and localization of calreticulin J. Immunol. 2013 190 5207 5215 10.4049/jimmunol.1300057 23596312 · DOI
  78. [98]Truxova I Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients Haematologica 2020 105 1868 1878 10.3324/haematol.2019.223933 31582537 PMC7327638 · DOI · Paper page
  79. [99]Fucikova J Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients Blood 2016 128 3113 3124 10.1182/blood-2016-08-731737 27802968 PMC5201098 · DOI · Paper page
  80. [100]Yang H Wang H Chavan SS Andersson U High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule Mol. Med. 2015 21 Suppl 1 S6 S12 10.2119/molmed.2015.00087 26605648 PMC4661054 · DOI
  81. [101]Zhu X Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation J. Clin. Invest. 2015 125 1098 1110 10.1172/JCI76344 25642769 PMC4362239 · DOI
  82. [102]Park JS High mobility group box 1 protein interacts with multiple Toll-like receptors Am. J. Physiol. Cell Physiol. 2006 290 C917 C924 10.1152/ajpcell.00401.2005 16267105 · DOI
  83. [105]Smith M Trial Watch: Toll-like receptor agonists in cancer immunotherapy Oncoimmunology 2018 7 e1526250 10.1080/2162402X.2018.1526250 30524908 PMC6279325 · DOI
  84. [106]Medzhitov R MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways Mol. Cell 1998 2 253 258 10.1016/S1097-2765(00)80136-7 9734363 · DOI
  85. [107]Gay NJ Symmons MF Gangloff M Bryant CE Assembly and localization of Toll-like receptor signalling complexes Nat. Rev. Immunol. 2014 14 546 558 10.1038/nri3713 25060580 · DOI · Paper page
  86. [108]Vigneron C Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced natural killer cell activity Oncoimmunology 2019 8 e1641391 10.1080/2162402X.2019.1641391 31646090 PMC6791422 · DOI
  87. [109]Nayagom B Immunogenic cell death in a combined synergic gene- and immune-therapy against cancer Oncoimmunology 2019 8 e1667743 10.1080/2162402X.2019.1667743 31741770 PMC6844315 · DOI
  88. [110]Bergmann C Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas J. Transl. Med. 2011 9 139 10.1186/1479-5876-9-139 21854645 PMC3170603 · DOI
  89. [111]Tittarelli A Toll-like receptor 4 gene polymorphism influences dendritic cell in vitro function and clinical outcomes in vaccinated melanoma patients Cancer Immunol. Immunother. 2012 61 2067 2077 10.1007/s00262-012-1268-7 22552381 PMC11029707 · DOI
  90. [112]Sprooten J Trial watch: dendritic cell vaccination for cancer immunotherapy Oncoimmunology 2019 8 e1638212 10.1080/2162402X.2019.1638212 31646087 PMC6791419 · DOI
  91. [113]Galluzzi L Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes Cell Death Differ. 2009 16 1093 1107 10.1038/cdd.2009.44 19373242 PMC2757140 · DOI
  92. [115]Anderson CM Macleod KF Autophagy and cancer cell metabolism Int. Rev. Cell Mol. Biol. 2019 347 145 190 10.1016/bs.ircmb.2019.06.002 31451213 PMC8211395 · DOI
  93. [116]Follo C Cheng Y Richards WG Bueno R Broaddus VC Autophagy facilitates the release of immunogenic signals following chemotherapy in 3D models of mesothelioma Mol. Carcinog. 2019 58 1754 1769 10.1002/mc.23050 31215708 · DOI
  94. [117]Burnstock G Physiology and pathophysiology of purinergic neurotransmission Physiol. Rev. 2007 87 659 797 10.1152/physrev.00043.2006 17429044 · DOI
  95. [118]Elliott MR Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance Nature 2009 461 282 286 10.1038/nature08296 19741708 PMC2851546 · DOI · Paper page
  96. [119]Ghiringhelli F Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors Nat. Med. 2009 15 1170 1178 10.1038/nm.2028 19767732 · DOI · Paper page
  97. [121]Swanson KV Deng M Ting JP The NLRP3 inflammasome: molecular activation and regulation to therapeutics Nat. Rev. Immunol. 2019 19 477 489 10.1038/s41577-019-0165-0 31036962 PMC7807242 · DOI · Paper page
  98. [122]Ohta A Sitkovsky M Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage Nature 2001 414 916 920 10.1038/414916a 11780065 · DOI
  99. [123]Stagg J CD73-deficient mice are resistant to carcinogenesis Cancer Res. 2012 72 2190 2196 10.1158/0008-5472.CAN-12-0420 22396496 · DOI
  100. [124]Allard B Allard D Buisseret L Stagg J The adenosine pathway in immuno-oncology Nat. Rev. Clin. Oncol. 2020 17 611 629 10.1038/s41571-020-0382-2 32514148 · DOI
  101. [126]Sistigu A Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy Nat. Med. 2014 20 1301 1309 10.1038/nm.3708 25344738 · DOI · Paper page
  102. [128]Khodarev NN Intracellular RNA sensing in mammalian cells: role in stress response and cancer therapies Int. Rev. Cell Mol. Biol. 2019 344 31 89 10.1016/bs.ircmb.2018.08.005 30798990 · DOI
  103. [129]Medler T Activating the nucleic acid-sensing machinery for anticancer immunity Int. Rev. Cell Mol. Biol. 2019 344 173 214 10.1016/bs.ircmb.2018.08.006 30798988 PMC6754183 · DOI
  104. [131]McLaughlin M Inflammatory microenvironment remodelling by tumour cells after radiotherapy Nat. Rev. Cancer 2020 20 203 217 10.1038/s41568-020-0246-1 32161398 · DOI
  105. [132]Motwani M Pesiridis S Fitzgerald KA DNA sensing by the cGAS-STING pathway in health and disease Nat. Rev. Genet. 2019 20 657 674 10.1038/s41576-019-0151-1 31358977 · DOI · Paper page
  106. [133]Kawasaki T Kawai T Discrimination between self and non-self-nucleic acids by the innate immune system Int. Rev. Cell Mol. Biol. 2019 344 1 30 10.1016/bs.ircmb.2018.08.004 30798985 PMC7105031 · DOI
  107. [134]Oh JH Sustained type I interferon reinforces NK cell-mediated cancer immunosurveillance during chronic virus infection Cancer Immunol. Res. 2019 7 584 599 10.1158/2326-6066.CIR-18-0403 30808680 · DOI
  108. [135]Bek S Targeting intrinsic RIG-I signaling turns melanoma cells into type I interferon-releasing cellular antitumor vaccines Oncoimmunology 2019 8 e1570779 10.1080/2162402X.2019.1570779 30906666 PMC6422402 · DOI
  109. [136]Takeda Y Type I interferon-independent dendritic cell priming and antitumor T cell activation induced by a Mycoplasma fermentans lipopeptide Front. Immunol. 2018 9 496 10.3389/fimmu.2018.00496 29593736 PMC5861346 · DOI
  110. [137]Muller E Toll-like receptor ligands and interferon-gamma synergize for induction of antitumor M1 macrophages Front. Immunol. 2017 8 1383 10.3389/fimmu.2017.01383 29123526 PMC5662546 · DOI
  111. [138]Gangaplara A Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment PLoS Pathog. 2018 14 e1006985 10.1371/journal.ppat.1006985 29672594 PMC5929570 · DOI
  112. [139]Vanpouille-Box C DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity Nat. Commun. 2017 8 15618 10.1038/ncomms15618 28598415 PMC5472757 · DOI · Paper page
  113. [140]Deng L STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors Immunity 2014 41 843 852 10.1016/j.immuni.2014.10.019 25517616 PMC5155593 · DOI · Paper page
  114. [141]Los GV Wood K The HaloTag: a novel technology for cell imaging and protein analysis Methods Mol. Biol. 2007 356 195 208 16988404
  115. [142]Los GV HaloTag: a novel protein labeling technology for cell imaging and protein analysis ACS Chem. Biol. 2008 3 373 382 10.1021/cb800025k 18533659 · DOI
  116. [143]Menger L Cardiac glycosides exert anticancer effects by inducing immunogenic cell death Sci. Transl. Med. 2012 4 143ra199 10.1126/scitranslmed.3003807 22814852 · DOI · Paper page
  117. [144]Pacheco A Merianda TT Twiss JL Gallo G Mechanism and role of the intra-axonal Calreticulin translation in response to axonal injury Exp. Neurol. 2020 323 113072 10.1016/j.expneurol.2019.113072 31669485 PMC6909931 · DOI
  118. [145]Gao G Zhu C Liu E Nabi IR Reticulon and CLIMP-63 regulate nanodomain organization of peripheral ER tubules PLoS Biol. 2019 17 e3000355 10.1371/journal.pbio.3000355 31469817 PMC6742417 · DOI
  119. [146]Fucikova J Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis Cancer Res. 2016 76 1746 1756 10.1158/0008-5472.CAN-15-1142 26842877 · DOI
  120. [147]Costa-Mattioli M Walter P The integrated stress response: from mechanism to disease Science 2020 368 eaat5314 10.1126/science.aat5314 32327570 PMC8997189 · DOI · Paper page
  121. [148]Hetz C Papa FR The unfolded protein response and cell fate control Mol. Cell 2018 69 169 181 10.1016/j.molcel.2017.06.017 29107536 · DOI
  122. [149]Bezu L eIF2α phosphorylation is pathognomonic for immunogenic cell death Cell Death Differ. 2018 25 1375 1393 10.1038/s41418-017-0044-9 29358668 PMC6113215 · DOI
  123. [150]Glimcher LH Lee AH Iwakoshi NN XBP-1 and the unfolded protein response (UPR) Nat. Immunol. 2020 21 963 965 10.1038/s41590-020-0708-3 32616861 · DOI
  124. [151]Hetz C The unfolded protein response: controlling cell fate decisions under ER stress and beyond Nat. Rev. Mol. Cell Biol. 2012 13 89 102 10.1038/nrm3270 22251901 · DOI
  125. [152]Rainbolt TK Frydman J Dynamics and clustering of IRE1alpha during ER stress Proc. Natl Acad. Sci. USA 2020 117 3352 3354 10.1073/pnas.1921799117 32019880 PMC7035497 · DOI
  126. [153]Hetz C Chevet E Harding HP Targeting the unfolded protein response in disease Nat. Rev. Drug Discov. 2013 12 703 719 10.1038/nrd3976 23989796 · DOI
  127. [154]Harding HP Zhang Y Ron D Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase Nature 1999 397 271 274 10.1038/16729 9930704 · DOI · Paper page
  128. [155]van Schadewijk A van’t Wout EF Stolk J Hiemstra PS A quantitative method for detection of spliced X-box binding protein-1 (XBP1) mRNA as a measure of endoplasmic reticulum (ER) stress Cell Stress Chaperones 2012 17 275 279 10.1007/s12192-011-0306-2 22038282 PMC3273559 · DOI
  129. [156]Hayashi A The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development J. Biol. Chem. 2007 282 34525 34534 10.1074/jbc.M704300200 17890727 · DOI
  130. [157]Prischi F Nowak PR Carrara M Ali MM Phosphoregulation of Ire1 RNase splicing activity Nat. Commun. 2014 5 3554 10.1038/ncomms4554 24704861 PMC3988810 · DOI
  131. [158]Reineke LC Dougherty JD Pierre P Lloyd RE Large G3BP-induced granules trigger eIF2α phosphorylation Mol. Biol. Cell 2012 23 3499 3510 10.1091/mbc.e12-05-0385 22833567 PMC3442399 · DOI
  132. [159]Dong Xda E High mobility group box I (HMGB1) release from tumor cells after treatment: implications for development of targeted chemoimmunotherapy J. Immunother. 2007 30 596 606 10.1097/CJI.0b013e31804efc76 17667523 · DOI
  133. [160]Zhao L Liu P Kepp O Kroemer G Methods for measuring HMGB1 release during immunogenic cell death Methods Enzymol. 2019 629 177 193 10.1016/bs.mie.2019.05.001 31727240 · DOI
  134. [161]Candolfi M Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity Clin. Cancer Res. 2009 15 4401 4414 10.1158/1078-0432.CCR-09-0155 19570774 PMC2769255 · DOI
  135. [162]Bommareddy PK Zloza A Rabkin SD Kaufman HL Oncolytic virus immunotherapy induces immunogenic cell death and overcomes STING deficiency in melanoma Oncoimmunology 2019 8 1591875 10.1080/2162402X.2019.1591875 31143509 PMC6527276 · DOI
  136. [163]Lei C Geng J Zhong L The association between plasma HMGB1 and sRAGE and clinical outcome in intracerebral hemorrhage J. Neuroimmunol. 2020 345 577266 10.1016/j.jneuroim.2020.577266 32470565 · DOI
  137. [164]Bruck E Prolonged elevation of plasma HMGB1 is associated with cognitive impairment in intensive care unit survivors Intensive Care Med. 2020 46 811 812 10.1007/s00134-020-05941-7 32103282 · DOI
  138. [165]Wang Y Urinary MCP-1HMGB1 increased in calcium nephrolithiasis patients and the influence of hypercalciuria on the production of the two cytokines Urolithiasis 2017 45 159 175 10.1007/s00240-016-0902-9 27393275 · DOI
  139. [166]Suzuki Y Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma Cancer Res. 2012 72 3967 3976 10.1158/0008-5472.CAN-12-0851 22700877 · DOI
  140. [167]Suren D HMGB1 expression in urothelial carcinoma of the bladder J. BUON 2018 23 1882 1886 30610817
  141. [168]Mohajertehran F Ayatollahi H Khazaeni K Shakeri MT Mohtasham N Overexpression of high-mobility motor box 1 in the blood and tissues of patients with head and neck squamous cell carcinoma Iran. J. Otorhinolaryngol. 2018 30 261 271 30245980 PMC6147264
  142. [169]Boncompain G Synchronization of secretory protein traffic in populations of cells Nat. Methods 2012 9 493 498 10.1038/nmeth.1928 22406856 · DOI
  143. [170]Boncompain, G. & Perez, F. Synchronizing protein transport in the secretory pathway. Curr. Protoc. Cell Biol.Chapter 15, Unit 15.19 (2012). 23208546
  144. [171]Dubyak GR Luciferase-assisted detection of extracellular ATP and ATP metabolites during immunogenic death of cancer cells Methods Enzymol. 2019 629 81 102 10.1016/bs.mie.2019.10.006 31727258 · DOI
  145. [172]Branchini BR Southworth TL A highly sensitive biosensor for ATP using a chimeric firefly luciferase Methods Enzymol. 2017 589 351 364 10.1016/bs.mie.2017.01.004 28336069 · DOI
  146. [173]Lundin A Thore A Analytical information obtainable by evaluation of the time course of firefly bioluminescence in the assay of ATP Anal. Biochem. 1975 66 47 63 10.1016/0003-2697(75)90723-X 1096673 · DOI
  147. [174]Lundin A Use of firefly luciferase in ATP-related assays of biomass, enzymes, and metabolites Methods Enzymol. 2000 305 346 370 10.1016/S0076-6879(00)05499-9 10812612 · DOI
  148. [175]Nagate, Y. et al. Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function. Leukemia.10.1038/s41375-020-0788-y (2020). PMC7787980 32203145 · DOI
  149. [176]Li XY Targeting CD39 in cancer reveals an extracellular ATP- and inflammasome-driven tumor immunity Cancer Discov. 2019 9 1754 1773 10.1158/2159-8290.CD-19-0541 31699796 PMC6891207 · DOI
  150. [177]Patel CH Leone RD Horton MR Powell JD Targeting metabolism to regulate immune responses in autoimmunity and cancer Nat. Rev. Drug Discov. 2019 18 669 688 10.1038/s41573-019-0032-5 31363227 · DOI
  151. [178]Altman BJ Stine ZE Dang CV From Krebs to clinic: glutamine metabolism to cancer therapy Nat. Rev. Cancer 2016 16 619 634 10.1038/nrc.2016.71 27492215 PMC5484415 · DOI · Paper page
  152. [179]Hoang G Udupa S Le A Application of metabolomics technologies toward cancer prognosis and therapy Int. Rev. Cell Mol. Biol. 2019 347 191 223 10.1016/bs.ircmb.2019.07.003 31451214 · DOI
  153. [180]Marceau F Roy C Bouthillier J Assessment of cation trapping by cellular acidic compartments Methods Enzymol. 2014 534 119 131 10.1016/B978-0-12-397926-1.00007-X 24359951 · DOI
  154. [181]Forveille S Quinacrine-mediated detection of intracellular ATP Methods Enzymol. 2019 629 103 113 10.1016/bs.mie.2019.05.050 31727236 · DOI
  155. [182]Vessey KA Ho T Jobling AI Wang AY Fletcher EL Fluorescent labeling and quantification of vesicular ATP release using live cell imaging Methods Mol. Biol. 2020 2041 209 221 10.1007/978-1-4939-9717-6_15 31646491 · DOI
  156. [183]Borden EC Interferons alpha and beta in cancer: therapeutic opportunities from new insights Nat. Rev. Drug Discov. 2019 18 219 234 10.1038/s41573-018-0011-2 30679806 · DOI
  157. [184]Formenti SC Radiotherapy induces responses of lung cancer to CTLA-4 blockade Nat. Med. 2018 24 1845 1851 10.1038/s41591-018-0232-2 30397353 PMC6286242 · DOI · Paper page
  158. [185]Becker-Merok A Ostli-Eilersten G Lester S Nossent J Circulating interferon-alpha2 levels are increased in the majority of patients with systemic lupus erythematosus and are associated with disease activity and multiple cytokine activation Lupus 2013 22 155 163 10.1177/0961203312468964 23213068 · DOI
  159. [186]Cherney DZ Scholey JW Sochett E Bradley TJ Reich HN The acute effect of clamped hyperglycemia on the urinary excretion of inflammatory cytokines/chemokines in uncomplicated type 1 diabetes: a pilot study Diabetes Care 2011 34 177 180 10.2337/dc10-1219 20841614 PMC3005484 · DOI
  160. [187]Leylek R Idoyaga J The versatile plasmacytoid dendritic cell: function, heterogeneity, and plasticity Int. Rev. Cell Mol. Biol. 2019 349 177 211 10.1016/bs.ircmb.2019.10.002 31759431 · DOI · Paper page
  161. [188]Moore EC Nanocomplex-based TP53 gene therapy promotes anti-tumor immunity through TP53- and STING-dependent mechanisms Oncoimmunology 2018 7 e1404216 10.1080/2162402X.2017.1404216 29900037 PMC5993490 · DOI
  162. [189]Diamond JM Exosomes shuttle TREX1-sensitive IFN-stimulatory dsDNA from irradiated cancer cells to DCs Cancer Immunol. Res 2018 6 910 920 10.1158/2326-6066.CIR-17-0581 29907693 PMC6072562 · DOI
  163. [190]Gry M Correlations between RNA and protein expression profiles in 23 human cell lines BMC Genomics 2009 10 365 10.1186/1471-2164-10-365 19660143 PMC2728742 · DOI
  164. [191]Liu Y Beyer A Aebersold R On the dependency of cellular protein levels on mRNA abundance Cell 2016 165 535 550 10.1016/j.cell.2016.03.014 27104977 · DOI · Paper page
  165. [192]Downey J RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to influenza A virus infection PLoS Pathog. 2017 13 e1006326 10.1371/journal.ppat.1006326 28410401 PMC5406035 · DOI
  166. [193]Sarkar MK Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa Ann. Rheum. Dis. 2018 77 1653 1664 10.1136/annrheumdis-2018-213197 30021804 PMC6185784 · DOI
  167. [195]Skopelja-Gardner S The early local and systemic Type I interferon responses to ultraviolet B light exposure are cGAS dependent Sci. Rep. 2020 10 7908 10.1038/s41598-020-64865-w 32404939 PMC7220927 · DOI
  168. [196]Demaria O STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity Proc. Natl Acad. Sci. USA 2015 112 15408 15413 10.1073/pnas.1512832112 26607445 PMC4687570 · DOI
  169. [197]Wu H Mumps virus-induced innate immune responses in mouse Sertoli and Leydig cells Sci. Rep. 2016 6 19507 10.1038/srep19507 26776505 PMC4725973 · DOI
  170. [198]Zhu W Pattern recognition receptor-initiated innate antiviral responses in mouse epididymal epithelial cells J. Immunol. 2015 194 4825 4835 10.4049/jimmunol.1402706 25840915 · DOI
  171. [199]Bordignon J Expression profile of interferon stimulated genes in central nervous system of mice infected with dengue virus Type-1 Virology 2008 377 319 329 10.1016/j.virol.2008.04.033 18570970 · DOI
  172. [200]Zhou H The oncolytic peptide LTX-315 triggers immunogenic cell death Cell Death Dis. 2016 7 e2134 10.1038/cddis.2016.47 26962684 PMC4823948 · DOI
  173. [201]Clifford JL Expression of protein mediators of type I interferon signaling in human squamous cell carcinoma of the skin Cancer Epidemiol. Biomark. Prev. 2000 9 993 997 11008921
  174. [202]Clifford JL Suppression of type I interferon signaling proteins is an early event in squamous skin carcinogenesis Clin. Cancer Res. 2002 8 2067 2072 12114405
  175. [203]Cooke SK Effects of the presence and absence of amino acids on translation, signaling, and long-term depression in hippocampal slices from Fmr1 knockout mice J. Neurochem. 2019 151 764 776 10.1111/jnc.14874 31539452 PMC6989092 · DOI
  176. [205]Coudert L Adjibade P Mazroui R Analysis of translation initiation during stress conditions by polysome profiling J. Vis. Exp. 2014 87 51164 PMC4193336 24893838
  177. [206]Kepp O A fluorescent biosensor-based platform for the discovery of immunogenic cancer cell death inducers Oncoimmunology 2019 8 1606665 10.1080/2162402X.2019.1606665 31413915 PMC6682369 · DOI
  178. [207]Han P Hanlon D Sobolev O Chaudhury R Edelson RL Ex vivo dendritic cell generation-A critical comparison of current approaches Int. Rev. Cell Mol. Biol. 2019 349 251 307 10.1016/bs.ircmb.2019.10.003 31759433 · DOI
  179. [208]Wculek SK Dendritic cells in cancer immunology and immunotherapy Nat. Rev. Immunol. 2020 20 7 24 10.1038/s41577-019-0210-z 31467405 · DOI
  180. [209]Bezu L Combinatorial strategies for the induction of immunogenic cell death Front. Immunol. 2015 6 187 25964783 PMC4408862
  181. [210]Feng M Phagocytosis checkpoints as new targets for cancer immunotherapy Nat. Rev. Cancer 2019 19 568 586 10.1038/s41568-019-0183-z 31462760 PMC7002027 · DOI
  182. [211]Chao MP Majeti R Weissman IL Programmed cell removal: a new obstacle in the road to developing cancer Nat. Rev. Cancer 2011 12 58 67 10.1038/nrc3171 22158022 · DOI
  183. [212]Hennessy EJ Parker AE O’Neill LA Targeting Toll-like receptors: emerging therapeutics? Nat. Rev. Drug Discov. 2010 9 293 307 10.1038/nrd3203 20380038 · DOI

Cited by

Sorted by citations

Authors
Fucikova, J., Kepp, O., Kasikova, L., Petroni, G., Yamazaki, T., Liu, P., Zhao, L., Spisek, R., Kroemer, G., & Galluzzi, L.
Affiliations
  • Charles University (CZ)
  • Inserm (FR)
  • Weill Cornell Medicine (US)
  • Karolinska University Hospital (SE)
  • Université Paris Cité (FR)
Corresponding author
  • Kroemer, Guido
  • Galluzzi, Lorenzo
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2020-11-26
Volume
11
Issue
11
Pages
1013-1013
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-020-03221-2
PMC
PMC7691519
OpenAlex
W3108774824
Cited by
1,138
References
29
Citations by year
2026: 200 · 2025: 251 · 2024: 235 · 2023: 242 · 2022: 150 · 2021: 59 · 2015: 1
FWCI
11.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (#BC180476P1, ZP-6177)
  • Leukemia and Lymphoma Society
  • Association pour la Recherche sur le Cancer
  • Seerave Foundation
  • E-Rare
  • European Commission (HORIZON2020)
  • Agence Nationale de la Recherche (ANR-16-ECVD-0008, E-Rare-2)
  • Fondation Leducq
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation pour la Recherche Médicale
  • Ligue Contre le Cancer
  • Institut Universitaire de France
  • Institut National Du Cancer
  • Institut Gustave-Roussy
  • European Research Area Network on Cardiovascular Diseases
  • Weill Cornell Medical College
  • Stand Up To Cancer (ZP-6177)
  • High-end Foreign Experts Recruitment Plan of China (GDW20171100085, GDW20181100051, GDW20171100085 and GDW20181100051)
  • Labex Immuno-Oncology
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
immunogenic cell death, damage-associated molecular patterns, calreticulin, ATP, annexin A1, type I interferon, HMGB1, autophagy, tumor immunogenicity, cancer immunotherapy, anticancer agents, precision oncology, combination therapy
MeSH terms
Immunogenic Cell Death, Humans, Immunotherapy, Neoplasms, Drug Discovery

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review