Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

Galluzzi, Lorenzo; Vitale, Ilio; Warren, Sarah; Adjemian, Sandy; Agostinis, Patrizia; Martinez, Aitziber Burque; Chan, Timothy A.; Coukos, George; Demaria, Sandra; Deutsch, Éric; Draganov, Dobrin; Edelson, Richard L.; Formenti, Silvia C.; Fučíková, Jitka; Gabriele, Lucia; Gaipl, Udo S.; Gameiro, Sofia R.; Garg, Abhishek D.; Golden, Encouse B.; Han, Jian; Harrington, Kevin; Hemminki, Akseli; Hodge, James W.; Hossain, Dewan Md Sakib; Illidge, Tim; Karin, Michael; Kaufman, Howard L.; Kepp, Oliver; Kroemer, Guido; Lasarte, Juan José; Loi, Sherene; Lotze, Michael T.; Manic, Gwenola; Merghoub, Taha; Melcher, Alan; Mossman, Karen; Prósper, Felipe; Rekdal, Øystein; Rescigno, María; Riganti, Chiara; Sistigu, Antonella; Smyth, Mark J.; Špíšek, Radek; Stagg, John; Strauss, Bryan E.; Tang, Daolin; Tatsuno, Kazuki; Gool, Stefaan Van; Vandenabeele, Peter; Yamazaki, Takahiro; Zamarin, Dmitriy; Zitvogel, Laurence; Cesano, Alessandra; Marincola, Francesco M.

doi:10.1136/jitc-2019-000337

Cited by 757 publications

(757 citation statements)

References 332 publications

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“…Both surface and soluble molecules are required to induce ICD in response to chemotherapeutic drugs such as anthracyclines, oxaliplatin, taxanes, alkylating agents, and proteasome inhibitors [2][3][4]. The exposure of calreticulin (CRT) on cell surface and the release of ATP and High Mobility Group Box 1 (HMGB1) protein are potent signals that engage dendritic cells (DCs), stimulate phagocytosis and antigen processing, and expand cytotoxic CD8 + T-lymphocytes (CTLs) with antitumor activity [2,5]. CRT, a chaperon protein usually residing within endoplasmic reticulum (ER), translocates to the plasmamembrane, bound to the ERp57 protein.…”

Section: Introductionmentioning

confidence: 99%

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Kopecka

Godel

Dei

et al. 2020

Cells

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Doxorubicin is a strong inducer of immunogenic cell death (ICD), but it is ineffective in P-glycoprotein (Pgp)-expressing cells. Indeed, Pgp effluxes doxorubicin and impairs the immunesensitizing functions of calreticulin (CRT), an “eat-me” signal mediating ICD. It is unknown if classical Pgp inhibitors, designed to reverse chemoresistance, may restore ICD. We addressed this question by using Pgp-expressing cancer cells, treated with Tariquidar, a clinically approved Pgp inhibitor, and R-3 compound, a N,N-bis(alkanol)amine aryl ester derivative with the same potency of Tariquidar as Pgp inhibitor. In Pgp-expressing/doxorubicin-resistant cells, Tariquidar and R-3 increased doxorubicin accumulation and toxicity, reduced Pgp activity, and increased CRT translocation and ATP and HMGB1 release. Unexpectedly, only R-3 promoted phagocytosis by dendritic cells and activation of antitumor CD8+T-lymphocytes. Although Tariquidar did not alter the amount of Pgp present on cell surface, R-3 promoted Pgp internalization and ubiquitination, disrupting its interaction with CRT. Pgp knock-out restores doxorubicin-induced ICD in MDA-MB-231/DX cells that recapitulated the phenotype of R-3-treated cells. Our work demonstrates that plasma membrane-associated Pgp prevents a complete ICD notwithstanding the release of ATP and HMGB1, and the exposure of CRT. Pharmacological compounds reducing Pgp activity and amount may act as promising chemo- and immunesensitizing agents.

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Section: Introductionmentioning

confidence: 99%

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Kopecka

Godel

Dei

et al. 2020

Cells

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“…ICD includes immunogenic apoptosis, necrosis/necroptosis, pyroptosis, and autophagic cell death. Endoplasmic reticulum (ER) stress response, PAMPs, and DAMPs play important roles in OV-induced ICD [70].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Recent studies demonstrated that genetically modified OVs, armed with a therapeutic gene, mediated clinical responses. FDA approved T-VEC was safe and, in advanced melanoma, resulted in a 10.8% complete response rate, significantly higher than systemic GM-CSF alone [70]. Other examples are poxvirus (Pexavec, TRICOM, TroVax) [74,75], and adenovirus (ONCOS-102) [76].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis

Schirrmacher¹

2020

Biomedicines

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This review compares cytotoxic drugs, targeted therapies, and immunotherapies with regard to mechanisms and side effects. Targeted therapies relate to small molecule inhibitors. Immunotherapies include checkpoint inhibitory antibodies, chimeric antigen receptor (CAR) T-cells, cancer vaccines, and oncolytic viruses. All these therapeutic approaches fight systemic disease, be it micro-metastatic or metastatic. The analysis includes only studies with a proven therapeutic effect. A clear-cut difference is observed with regard to major adverse events (WHO grades 3–4). Such severe side effects are not observed with cancer vaccines/oncolytic viruses while they are seen with all the other systemic therapies. Reasons for this difference are discussed.

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“…A recently described phenomenon, termed immunogenic cell death (ICD) (5,6), is a form of cell death that induces an immune response from the host. ICD is distinguished from classical apoptosis and other non-immunogenic or tolerogenic forms of cell death by several hallmarks, including release of ATP and HMGB1 and surface exposure of calreticulin (5)(6)(7). In cancer patients, ICD-based anti-tumor immune responses are linked to beneficial outcomes produced by some conventional chemotherapeutic agents (8)(9)(10)(11).…”

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confidence: 99%

Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer

Han

Bennett

Irvine

et al. 2020

Preprint

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We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2×4/P2×7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p=0.03) and promoted complete responses (p<0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p=0.03) and adjuvant treatment (p<0.001), and potential cures in metastatic disease (p<0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p=0.007) and metastatic settings (p<0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting ‘cold’ tumors ‘hot’, thus represents a rational mechanistic partner with checkpoint blockade.

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Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

Cited by 757 publications

References 332 publications

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis

Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer

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