Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy
Abstract
Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy.
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Intratumoral presence of CD8+ T cells is linked to a type-I interferon transcriptional signature.
“multiple clinical observations have linked intratumoral presence of CD8+ T cells to a type-I interferon (IFN) transcriptional signature14–16.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [16]
Type-I IFNs are important in the initiation of spontaneous and iatrogenic antitumor immune T cell responses.
“several preclinical studies have confirmed the important function of type-I IFNs in the initiation of spontaneous and iatrogenic antitumor immune T cell responses”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [16]
IFN-β induction in tumor cells can exert direct effects both on tumor cells and APCs.
“IFN-β induction in tumor cells can exert direct effects both on tumor cells as well as APCs16,47.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [16]
Defects in dsRNA/dsDNA detection (Tlr3−/−, TREX1 overexpression) or Ifnar1 deletion abolish immunogenicity of cell death triggered by various ICD inducers.
“Accordingly, defects in dsRNA or dsDNA detection imposed by genetic interventions, including the Tlr3−/− genotype and the transgene-driven overexpression of the three prime repair exonuclease 1 (TREX1), as well as the deletion of Ifnar1 from cancer or host cells, abolish the immunogenicity of cell death triggered by various ICD inducers [854, 873].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [873]
Type I IFN is produced by cancer cells undergoing ICD via TLR3 detection of endogenous dsRNA or cGAS detection of dsDNA.
“Type I IFN is produced by cancer cells succumbing to ICD by a mechanism involving the detection of endogenous dsRNA by TLR3 [873], or double-stranded DNA (dsDNA) by cGAS [854, 905, 906].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [873]
Type I IFN activates autocrine/paracrine signaling in malignant cells, inducing ISGs including CXCL10.
“Besides mediating broad immunostimulatory effects on immune cells expressing IFNAR1 [520, 907], type I IFN reportedly activates an autocrine/paracrine signaling pathway in malignant cells, culminating with the expression of a spectrum of IFN-stimulated genes (ISGs) that includes the chemoattractant for T cells C-X-C motif chemokine ligand 10 (CXCL10) [873].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [873]
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References 73 · Cited by 1,042
- Authors
- Sistigu, A., Yamazaki, T., Vacchelli, E., Chaba, K., Enot, D. P., Adam, J., Vitale, I., Goubar, A., Baracco, E. E., Remédios, C., Fend, L., Hannani, D., Aymeric, L., Ma, Y., Niso-Santano, M., Kepp, O., Schultze, J. L., Tüting, T., Belardelli, F., Bracci, L., La Sorsa, V., Ziccheddu, G., Sestili, P., Urbani, F., Delorenzi, M., Lacroix-Triki, M., Quidville, V., Conforti, R., Spano, J.-P., Pusztai, L., Poirier-Colame, V., Delaloge, S., Penault-Llorca, F., Ladoire, S., Arnould, L., Cyrta, J., Dessoliers, M.-C., Eggermont, A., Bianchi, M. E., Pittet, M., Engblom, C., Pfirschke, C., Préville, X., Uzè, G., Schreiber, R. D., Chow, M. T., Smyth, M. J., Proietti, E., André, F., Kroemer, G., & Zitvogel, L.
- Affiliations
- Inserm (FR)
- Institut Gustave Roussy (FR)
- Instituto Nazionale Tumori Regina Elena (IT)
- Transgene (France) (FR)
- University of Bonn (DE)
- University Hospital Bonn (DE)
- Istituto Superiore di Sanità (IT)
- SIB Swiss Institute of Bioinformatics (CH)
- Pitié-Salpêtrière Hospital (FR)
- Yale University (US)
- Université Clermont Auvergne (FR)
- Université Paris-Saclay (FR)
- IRCCS Ospedale San Raffaele (IT)
- Massachusetts General Hospital (US)
- Washington University in St. Louis (US)
- QIMR Berghofer Medical Research Institute (AU)
- The University of Queensland (AU)
- Corresponding author
- Kroemer, Guido
- Zitvogel, Laurence
- ORCID
- Sistigu, Antonella
- Yamazaki, Takahiro
- Vacchelli, Erika
- Adam, Julien
- Vitale, Ilio
- Remédios, Catarina
- Hannani, Dalil
- Aymeric, Laetitia
- Ma, Yuting
- Kepp, Oliver
- Schultze, Joachim L
- Tüting, Thomas
- Belardelli, Filippo
- Bracci, Laura
- Ziccheddu, Giovanna
- Sestili, Paola
- Urbani, Francesca
- Delorenzi, Mauro
- Spano, Jean-Philippe
- Pusztai, Lajos
- Delaloge, Suzette
- Penault-Llorca, Frederique
- Ladoire, Sylvain
- Arnould, Laurent
- Cyrta, Joanna
- Eggermont, Alexander
- Bianchi, Marco E
- Engblom, Camilla
- Pfirschke, Christina
- Préville, Xavier
- Schreiber, Robert D
- Smyth, Mark J
- Proietti, Enrico
- André, Fabrice
- Kroemer, Guido
- Zitvogel, Laurence
- Venue
- Nature Medicine
- Published
- 2014-10-26
- Volume
- 20
- Issue
- 11
- Pages
- 1301-1309
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2081796577
- Cited by
- 1,042
- References
- 73
- Citations by year
- 2026: 50 · 2025: 60 · 2024: 104 · 2023: 110 · 2022: 92 · 2021: 112 · 2020: 109 · 2019: 99 · 2018: 87 · 2017: 79 · 2016: 80 · 2015: 51 · 2014: 8 · 2013: 1
- FWCI
- 33.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- HAL (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Institutional Repository University of Extremadura (University of Extremadura) (submittedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- European Commission
- Istituto Superiore di Sanità
- Ligue Contre le Cancer
- Institut Gustave-Roussy
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- type I interferon signaling, anthracyclines, chemotherapy efficacy, TLR3, IFNAR, CXCL10, viral mimicry, breast cancer, chemotherapy response prediction, innate immunity
- MeSH terms
- Animals, Breast Neoplasms, Doxorubicin, Female, Humans, Immunocompetence, Interferon Type I, Mice, Inbred C57BL, Neoplasm Metastasis, RNA, RNA, Messenger, Signal Transduction, Gene Expression Regulation, Neoplastic, Treatment Outcome, Anthracyclines, Neoadjuvant Therapy, Adaptor Proteins, Vesicular Transport, Receptors, Pattern Recognition, Toll-Like Receptor 3, Receptor, Interferon alpha-beta, Chemokine CXCL10, Myxovirus Resistance Proteins
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