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Cellular Cytotoxicity Is a Form of Immunogenic Cell Death Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2019-000325 on 26 March 2020. Downloaded from Cellular cytotoxicity is a form of immunogenic cell death Luna Minute,1,2 Alvaro Teijeira,1,2,3 Alfonso R Sanchez- Paulete,1,2 Maria C Ochoa,1,2,3 Maite Alvarez,1,2 Itziar Otano,1,2 Iñaki Etxeberrria,1,2 Elixabet Bolaños,1,2 Arantza Azpilikueta,1,2 Saray Garasa,1,2 Noelia Casares,1,2 2,4 1,2,4 1,2,3 Jose Luis Perez Gracia, Maria E Rodriguez- Ruiz, Pedro Berraondo , 1,2,3,4 Ignacio Melero To cite: Minute L, Teijeira A, ABSTRACT activated cytotoxic lymphocytes as a result of Sanchez- Paulete AR, et al. Background The immune response to cancer is often pores formed by polyperforin that permit the Cellular cytotoxicity is a form of conceptualized with the cancer immunity cycle. An essential entrance of granzyme B to activate caspase- immunogenic cell death. Journal step in this interpretation is that antigens released by dying 1 2 for ImmunoTherapy of Cancer dependent apoptosis. Furthermore, acti- tumors are presented by dendritic cells to naive or memory 2020;8:e000325. doi:10.1136/ vated cytotoxic cells exhibit tumor necrosis T cells in the tumor- draining lymph nodes. Whether tumor jitc-2019-000325 factor- family proapoptotic ligands such as cell death resulting from cytotoxicity, as mediated by T cells 3 or natural killer (NK) lymphocytes, is actually immunogenic Fas ligand (FASL) and TNF- related apop- ► Additional material is 4 currently remains unknown. tosis inducing ligand (TRAIL) that may elicit published online only. To view 1 please visit the journal online Methods In this study, tumor cells were killed by antigen- processes of apoptosis in the tumor cells. (http:// dx. doi. org/ 10. 1136/ jitc- specific -T cell receptor (TCR) transgenic CD8 T cells or Following contact with cytotoxic effector 2019- 000325). activated NK cells. Immunogenic cell death was studied cells, target- cells undergo loss of viability and analyzing the membrane exposure of calreticulin and the progressive disruption of their structures PB and IM are joint senior release of high mobility group box 1 (HMGB1) by the dying and organelles. These cellular remains are authors. tumor cells. Furthermore, the potential immunogenicity of the referred to as dead cells and target- cell debris. tumor cell debris was evaluated in immunocompetent mice Accepted 01 March 2020 Under normal circumstances, apoptosis is challenged with an unrelated tumor sharing only one tumor- associated antigen and by class I major histocompatibility considered a form of immunologically silent complex (MHC)- multimer stainings. Mice deficient in programmed cell death. In tumor immu- Batf3, Ifnar1 and Sting1 were used to study mechanistic notherapy, it becomes important to know if ► http:// dx. doi. org/ 10. 1136/ requirements. cytotoxicity would be tolerogenic or, on the jitc- 2020- 000528 Results We observe in cocultures of tumor cells and effector contrary, immunogenic to sustain and diver- http://jitc.bmj.com/ cytotoxic cells, the presence of markers of immunogenic sify the immune response. In fact, immunoge- cell death such as calreticulin exposure and soluble HMGB1 nicity of tumor cell death coupled to release © Author(s) (or their protein. Ovalbumin (OVA)- transfected MC38 colon cancer of intracellular tumor antigens has been employer(s)) 2020. Re- use cells, exogenously pulsed to present the gp100 epitope are postulated in the so-called cancer immunity permitted under CC BY- NC. No killed in culture by mouse gp100- specific TCR transgenic commercial re- use. See rights 5 6 CD8 T cells. Immunization of mice with the resulting cycle. and permissions. Published by Immunogenic versus non- immunogenic on September 23, 2021 by guest. Protected copyright. BMJ. destroyed cells induces epitope spreading as observed by detection of OVA- specific T cells by MHC multimer staining death of tumor cells has been extensively 1Program of Immunology and rejection of OVA+ EG7 lymphoma cells. Similar results investigated by the groups of Kroemer et and Immunotherapy, Cima 7 8 9 Universidad de Navarra, were observed in mice immunized with cell debris generated al. Following incisive experiments in mice Pamplona, Spain by NK- cell mediated cytotoxicity. Mice deficient inBatf3 - which correlated with clinical findings, 2Navarra Institute for Health dependent dendritic cells (conventional dendritic cells type 1, immunogenic cell death was categorized Research (IDISNA), Pamplona, cDC1) fail to develop an anti- OVA response when immunized as being able to enhance T-cell recognition Spain with tumor cells killed by cytotoxic lymphocytes. In line with 3 of tumor antigens thereby delaying tumor Centro de Investigación this, cultured cDC1 dendritic cells uptake and can readily Biomédica en Red de Cáncer growth in immunocompetent but not in cross- present antigen from cytotoxicity- killed tumor cells to 10 (CIBERONC), Madrid, Spain cognate CD8+ T lymphocytes. immunodeficient mice. Mechanistic and 4Departments of Oncology and Conclusion These results support that an ongoing correlative experiments linked immunogenic Immunology, Clínica Universidad cell death to the endoplasmic reticulum de Navarra, Pamplona, Spain cytotoxic antitumor immune response can lead to immunogenic tumor cell death. stress response, and to the release or expo- Correspondence to sure of eat-me signals and alarmins that act Dr Ignacio Melero; BACKGROUND on dendritic cells to induce functional matu- imelero@ unav. es Antitumor immunity largely relies on effector ration into cells efficiently presenting tumor 1 11 Dr Pedro Berraondo; cytotoxic T or natural killer (NK) cells. antigens. Calreticulin exposure on the pberraondol@ unav. es Tumor cells may succumb on contact with plasma membrane,12 adenosine triphosphate Minute L, et al. J Immunother Cancer 2020;8:e000325. doi:10.1136/jitc-2019-000325 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2019-000325 on 26 March 2020. Downloaded from (ATP) release,13 14 high mobility group box 1 (HMGB1) to those shown in figure 1 with MC38OVA without EGFR release,15 extracellular mitochondrial formyl peptides16 were performed rendering comparable results. OVA are considered hallmarks of immunogenic cell death.10 expression was confirmed by intracellular OVA staining These findings are reminiscent of the danger model (ab85584, Abcam, Cambridge, UK) and real- time PCR. as postulated by Matzinger, which predicts that factors The MC38hEGFROVA, EG7, MC38, B16OVA, CHO released on tissue damage or cell stress are responsible FLT3- L FLAG cell lines were maintained at 37°C in 5% for immunogenicity.17 18 These are termed damage- CO2 and were grown in Roswell Park Memorial Institute associated molecular patterns (DAMPs).19 medium (RPMI) Medium 1640+Glutamax (Gibco Invit- The main inherent mechanism to turn on and sustain rogen, Carlsbad, California, USA) containing 10% heat- CD8 T- cell immunity is tumor-antigen cross- priming as inactivated fetal bovine serum (FBS) (Gibco), 100 IU/mL mediated by basic leucine zipper ATF- like transcription penicillin and 100 µg/mL streptomycin (Gibco) and 50 factor 3 (BATF3)- dependent conventional dendritic cells µM 2- Mercaptoethanol (Gibco). The MC38hEGFROVA 20 21 type 1 (cDC1) dendritic cells. These cells are able to cell line was grown with 6 µg/mL of Puromycin (Gibco) capture antigens from cell-death- associated debris and and 400 µg/mL of Geneticin (Gibco). To avoid loss of present such exogenous antigens via the major histocom- transgene expression, B16OVA and EG7 were maintained patibility complex (MHC) class I in the context of both with 400 µg/mL of Geneticin. 20 21 costimulation and interleukin-12 (IL-12) production. The HT29 cell line was cultured as other cells but Of note, these cDC1 cells closely cooperate with NK cells without 2-mercaptoethanol supplementation in the in the tumor microenvironment to elicit antitumor culture medium. 22 23 immunity. X-63 granulocyte macrophage- colony stimulating factor Our quest in this study was to ascertain if cytotoxicity as (GM-CSF) was grown in Iscove’s modified Dulbecco mediated by CD8 T cells or NK cells is a form of immu- medium (Sigma-Aldrich, St. Louis, Missouri, USA) nogenic cell death or not. Multiple lines of experimental supplemented with 1 mg/mL of Geneticin with 5% FCS, evidence laid before us in mouse models unequivocally 100 IU/mL penicillin and 100 µg/mL streptomycin. show that cytotoxicity is indeed a form of immunogenic cell death, since the remains of killed cells efficaciously Murine lymphocyte activation induce antitumor immunity. Spleens from euthanized Pmel-1 mice were excised and splenocytes isolated mechanically and cultured at a concentration of 1.5×106/mL for 48 hours with 100 METHODS ng/mL of human gp100 (KVPRNQDWL, RP20344, Mice and cell lines 25-33 GenScript, Piscataway, New Jersey, USA). After 48 hours, Experiments involving mice were approved by the Ethics we added fresh media and 30 IU/mL of IL-2 (Proleukin, Committee of the University of Navarra. C57BL/6 Novartis) and kept the culture for 48 hours. mice (5–8 weeks old, female) were obtained from To generate murine activated NK cells, we injected at a http://jitc.bmj.com/ Envigo (Huntingdon, Cambridgeshire, UK) and main- high hydrostatic pressure into the tail vein of RAG1 mice tained in the animal facility of Cima Universidad de 28 tm1Kmm/J gt/J 10 µg of Apo-Sushi- IL-15 expressing plasmid in 2 mL of Navarra. C57BL/6 Batf3 (Batf3KO), Tmem173 o/o physiological saline solution. We harvested spleens after (STINGKO), interferon-α (IFNα)/bR (IFNARKO), a 3 days and isolated murine NK cells by negative selection C.129S7(B6)Tag1tm1Mom/J (RAG1), B6.Cg- Thy1 /CyTg(T- craTcrb)8Rest/J (Pmel-1),24 C57BL/6-Tg(TcraTcrb)1100M- following the manufacturer’s instructions (NK Cell Isola- on September 23, 2021 by guest. Protected copyright. jb/J (OT- I), C57Bl/6 Tg14(act/EGFP)Osby (OT- I- enhanced tion Kit II mouse, Miltenyi Biotec, Bergisch Gladbach, green fluorescent protein (EGFP)) mice were bred at Germany).
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