Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy
Abstract
Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.
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Extracellular HMGB1 is required for the immunogenicity of ICD and binds to TLR-4 on DC to mediate cross-presentation efficiency.
“Extracellular HMGB1 is required for the immunogenicity of ICD. It binds to the Toll-like receptor 4 (TLR-4) on the surface of DC and mediates cross-presentation efficiency [39].”
From Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma (2015) · cites this paper as [39]
Six DAMPs have been mechanistically linked to perception of RCD as immunogenic: CALR, ATP, HMGB1, type I IFN, cancer cell-derived nucleic acids, and ANXA1.
“So far, six DAMPs have been mechanistically linked to the perception of RCD as immunogenic: (1) calreticulin (CALR) [865, 866], (2) ATP [867–869], (3) high-mobility group box 1 (HMGB1) [870–872], (4) type I IFN [854, 873, 874], (5) cancer cell-derived nucleic acids [864, 875], and (6) annexin A1 (ANXA1) [876].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [870]
HMGB1-TLR4 ligation on DCs promotes antigen processing and cross-presentation but does not induce DC maturation, which is mainly stimulated by RAGE.
“In particular, the ligation of HGMB1 to TLR4 on DCs promotes antigen processing and cross-presentation, yet does not induce DC maturation, which is mainly stimulated by RAGE [870, 916].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [870]
RCD is not perceived as immunogenic when cancer cells lack HMGB1 or ANXA1, or host lacks TLR4 or FPR1.
“In line with these observations, RCD is not perceived as immunogenic when cancer cells are depleted of HMGB1 or ANXA1, as well as when the host lacks TLR4 or FPR1 [870, 876].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [870]
During radiotherapy or chemotherapy, immune responses may be biased toward tumor antigens rather than normal self-antigens.
“Consequently, during radiotherapy or chemotherapy in which the tumor cells are induced to die, immune responses may be biased towards a response against the tumor antigens rather than normal self-antigens, to which the immune system has been tolerized 7,27,28.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [28]
In early-stage breast cancer patients treated with chemotherapy, lower metastasis-free survival was associated with a TLR4 polymorphism that affects binding of HMGB1 to TLR4.
“The clinical importance of this finding was suggested by the fact that, in early-stage breast cancer patients who were treated with chemotherapy, lower metastasis-free survival was associated with a TLR4 polymorphism that affects binding of HMGb1 to TLR4 (REF. 115).”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [115]
TLR4 signalling is important for dendritic cell-mediated cross-presentation of tumour antigens from dying, chemotherapy-treated tumour cells and involves HMGB1 release from the dying cells.
“TLR4 signalling was found to be important for dendritic cell-mediated cross-presentation of tumour antigens from dying, chemotherapy-treated tumour cells and involved HMGb1 release from the dying cells115.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [115]
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BackgroundSelf-citationDNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity
Vanpouille-Box, C., Alard, A., Aryankalayil, M. J., Sarfraz, Y., Diamond, J. M., Schneider, R. J., Inghirami, G., Coleman, C. N., Formenti, S. C., & Demaria, S. (2017) · Nature Communications · doi:10.1038/ncomms15618 · Cited by 1,834 · see citing works
Nanotechnology for Multimodal Synergistic Cancer Therapy
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How dying cells alert the immune system to danger
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“HMGB1 was also shown to have a role in the tumour immunity that results from chemotherapy- and radiotherapy-induced cell death by selective inhibition with neutralizing antibodies or RNA”
BackgroundImmunological aspects of cancer chemotherapy
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Mechanisms of Cisplatin Nephrotoxicity
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“Accordingly, tumor-bearing TLR4 deficient mice had reduced responses to chemotherapy and radiation therapy compared to WT mice [225].”
BackgroundResultImmunological effects of conventional chemotherapy and targeted anticancer agents
Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L., & Kroemer, G. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.10.012 · Cited by 1,530 · see citing works
“…(3) by the pharmacological or genetic inhibition of immunostimulatory cytokines including type I IFN, IFNg, IL-1b and IL-17, or their receptors (Apetoh et al., 2007; Ghiringhelli et al., 2009; Ma et al., 2011b; Sistigu et al., 2014); and (4) by the pharmacological or genetic interference with…”
BackgroundInfluentialMacrophages, innate immunity and cancer: balance, tolerance, and diversity
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“It has now been shown that dying tumor cells can be cross presented by dendritic cells and trigger a protective immune response via a TLR4MyD88 pathway [62].”
BackgroundTumour-intrinsic resistance to immune checkpoint blockade
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HMGB1 and RAGE in Inflammation and Cancer
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HMGB1 is a therapeutic target for sterile inflammation and infection
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Immunogenic cell stress and death
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Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade
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Damage-associated molecular patterns in inflammatory diseases
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“The release of HMGB1 from dying tumor cells increased the presentation of tumor antigens and regulated the TLR4-dependent immune response (88).”
BackgroundFerroptosis at the crossroads of cancer-acquired drug resistance and immune evasion
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“This hypothesis was derived from preclinical data demonstrating that the efficacy of some cancer therapies is related to the creation of a favorable immune microenvironment [5, 8].”
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Self-citationTumors as Organs: Complex Tissues that Interface with the Entire Organism
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“…response is also important for an efficient response to chemotherapy and radiation therapy: a high-mobility group box-1 protein that is released by dying cancer cells after therapy interacts with TLR4 on dendritic cells, resulting in efficient cytotoxic T-cell activation (Apetoh et al., 2007).”
Apoptotic cell clearance: basic biology and therapeutic potential
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Immunogenic and tolerogenic cell death
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“Consequently, during radiotherapy or chemotherapy in which the tumour cells are induced to die, immune responses can be biased towards a response against the tumour (altered self) antigens rather than normal self antigens, to which the immune system has been tolerize”
BackgroundSelf-citationImmunogenic death of colon cancer cells treated with oxaliplatin
Tesnière, A., Schlemmer, F., Boige, V., Kepp, O., Martins, I., Ghiringhelli, F., Aymeric, L., Michaud, M., Apétoh, L., Barault, L., et al. (2009) · Oncogene · doi:10.1038/onc.2009.356 · Cited by 1,177 · see citing works
“Indeed, dying cells release HMGB1 into the extracellular milieu in response to most chemotherapeutic agents (Apetoh et al., 2007a, b), and neutralization or depletion of HMGB1 abolishes the immunogenicity of cell death (Apetoh et al., 2007b).”
BackgroundResultInfluentialSelf-citationConsensus guidelines for the definition, detection and interpretation of immunogenic cell death
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“46 180–182 180 For Open access 194 195 AGER, advanced glycosylation end-product specific receptor; AIM2, absent in melanoma 2 ; ANXA1, annexin A1; APC, antigen-presenting cell; CALR, calreticulin; CCL, C-C motif chemokine ligand 2; CGAS, cyclic GMP-AMP synthase; CLEC9A, C-type lectin domain containing 9A; CXCL1, C- X-…”
InfluentialSelf-citationLi, W., Yang, J., Luo, L., Jiang, M., Qin, B., Yin, H., Zhu, C., Yuan, X., Zhang, J., Luo, Z., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11269-8 · Cited by 1,129 · see citing works
Detection of immunogenic cell death and its relevance for cancer therapy
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Self-citationRadiotherapy and immunotherapy: a beneficial liaison?
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Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift
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“For instance, data suggest that patients carrying a Toll-like receptor 4 loss-of-function allele that cannot bind to HMGB1 have a worse outcome after chemotherapy and radiation (23).”
BackgroundPitt, J. M., Vétizou, M., Daillère, R., Roberti, M. P., Yamazaki, T., Routy, B., Lepage, P., Boneca, I. G., Chamaillard, M., Kroemer, G., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.001 · Cited by 1,040 · see citing works
Self-citationDecoding cell death signals in liver inflammation
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“Furthermore, the circulating levels of IL-33 are elevated in patients 3 vol. 59 j 583–594 589 Fig.”
BackgroundInfluentialSelf-citationApoptosis, autophagy, necroptosis, and cancer metastasis
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“Once released, HMGB1 activates dendritic cells by engaging Toll-like receptor 4, which triggers an intense antitumor immune response and restricts metastasis [79,80].”
BackgroundNanoparticle‐Mediated Immunogenic Cell Death Enables and Potentiates Cancer Immunotherapy
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Systemic effects of local radiotherapy
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“The recent identification of two mediators of this process, calreticulin (CRT) and high-mobility group protein B1 (HMGB1), has shed light on the mechanism by which the irradiated tumor becomes a robust source of antigens for an in situ auto-vaccination [5,34].”
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Harnessing innate immunity in cancer therapy
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Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy
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“Our results are in accordance with previous findings that TLR4 can promote DC tumor antigen cross-presentation and CD8 T cell activation after immunogenic tumor cell death (Apetoh et al., 2007) and that tumor-infiltrating DCs can be key regulators of antitumor immunity (Broz et al.”
InfluentialSelf-citationCombination cancer immunotherapies tailored to the tumour microenvironment
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Targeting immunogenic cell death in cancer
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“Accumulating evidence indicates that several chemotherapeutic drugs are more efficient against tumors that are implanted in immunocompetent, with respect to immunodeficient, hosts.(1)”
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Dendritic Cells and Cancer Immunity
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Microbiota: a key orchestrator of cancer therapy
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Inflammatory microenvironment remodelling by tumour cells after radiotherapy
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“A recent study showed that the TLR4 signalling pathway can mediate such a signa”
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“Proper localized RT given at appropriate doses and scheduling may tip the balance in favor of antitumor immunity both through endogenous priming mechanisms and in combination with immunotherapy (2, 3, 9).”
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Self-citationRole of Macrophage Targeting in the Antitumor Activity of Trabectedin
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“…et al., 2011; Duluc et al., 2009; Guiducci et al., 2005; Rolny et al., 2011), deletion by killing or blocking of recruitment (DeNardo et al., 2011; Qian et al., 2011; van Rooijen and van Kesteren-Hendrikx, 2003; Zhang et al., 2010), and modulation by chemotherapeutic agents (Apetoh et al., 2007).”
BackgroundDifferential macrophage programming in the tumor microenvironment
Ruffell, B., Affara, N. I., & Coussens, L. M. (2012) · Trends in Immunology · doi:10.1016/j.it.2011.12.001 · Cited by 855 · see citing works
“for generating an adaptive immune response following cytotoxic therapies through TLR4 recognition of HMGB1 [116], both TLR4 and TLR2 signaling promote growth of cell lines in the lung through induced TNFα production by macrophages [117, 118].”
InfluentialMechanisms of pre‐apoptotic calreticulin exposure in immunogenic cell death
Panaretakis, T., Kepp, O., Brockmeier, U., Tesniere, A., Bjorklund, A., Chapman, D. C., Durchschlag, M., Joza, N., Pierron, G., van Endert, P., et al. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.1 · Cited by 848 · see citing works
“…evidence indicates that several chemothera- peutic agents, as well as radiotherapy, are more efficient against tumours that are implanted in immunocompetent hosts than against the same tumours growing on immuno- deficient mice (Casares et al, 2005; Apetoh et al, 2007; Obeid et al, 2007a).”
BackgroundInfluentialSelf-citationConsensus guidelines for the detection of immunogenic cell death
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“Huang B, Sikorski R, Kirn DH, Thorne SH. Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1.”
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The role of myeloid cells in cancer therapies
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The Interplay of Immunotherapy and Chemotherapy: Harnessing Potential Synergies
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Clinical significance of tumor-infiltrating lymphocytes in breast cancer
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“[44].”
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CD24 and Siglec-10 Selectively Repress Tissue Damage–Induced Immune Responses
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Toll-like receptors and cancer
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“In sterile sites, TLRs are likely to be activated by endogenous ligands that are derived from necrotic cells, such as HMGB1 (Ref”
BackgroundRole of Local Radiation Therapy in Cancer Immunotherapy
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Therapeutic vaccines for cancer: an overview of clinical trials
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Self-citationIdentification of a dendritic cell receptor that couples sensing of necrosis to immunity
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HMGB1: Endogenous Danger Signaling
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“These findings are validated further by the observation that node positive breast cancer patients carrying a loss of function TLR4 allele tend to relapse more quickly after treatment with chemo-radiation as compared to patients with wild-type TLR4 alleles (107,108).”
ResultPattern Recognition Receptors and the Host Cell Death Molecular Machinery
Amarante-Mendes, G. P., Adjemian, S., Branco, L. M., Zanetti, L. C., Weinlich, R., & Bortoluci, K. R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02379 · Cited by 759 · see citing works
“Indeed, a broad range of receptors, including PRR, sense these DAMPs and alert the immune system by inducing immune cell migration, increasing phagocytosis by macrophages and DCs, stimulating the production of pro-inflammatory cytokines or even contributing to the maturation of DCs, among other key functions (72, 80,…”
BackgroundGut microbiota in colorectal cancer development and therapy
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The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer
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Immunogenic cell death in cancer therapy: Present and emerging inducers
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Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy
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- Authors
- Apetoh, L., Ghiringhelli, F., Tesniere, A., Obeid, M., Ortiz, C., Criollo, A., Mignot, G., Maiuri, M. C., Ullrich, E., Saulnier, P., Yang, H., Amigorena, S., Ryffel, B., Barrat, F. J., Saftig, P., Levi, F., Lidereau, R., Nogues, C., Mira, J.-P., Chompret, A., Joulin, V., Clavel-Chapelon, F., Bourhis, J., André, F., Delaloge, S., Tursz, T., Kroemer, G., & Zitvogel, L.
- Affiliations
- Université Paris-Sud (FR)
- Feinstein Institute for Medical Research (US)
- Centre National de la Recherche Scientifique (FR)
- Dynavax Technologies (United States) (US)
- Inserm (FR)
- Corresponding author
- Kroemer, Guido
- Zitvogel, Laurence
- ORCID
- Venue
- Nature Medicine
- Published
- 2007-08-19
- Volume
- 13
- Issue
- 9
- Pages
- 1050-1059
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2093424661
- Cited by
- 3,056
- References
- 49
- Citations by year
- 2026: 133 · 2025: 110 · 2024: 133 · 2023: 205 · 2022: 183 · 2021: 188 · 2020: 217 · 2019: 152 · 2018: 172 · 2017: 182 · 2016: 172 · 2015: 188 · 2014: 158 · 2013: 193 · 2012: 165
- FWCI
- 44.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- TLR4, HMGB1, alarmins, dendritic cells, MyD88, cancer cell death, antitumor immunity, T cell immunity, cross-presentation, immunoadjuvant, breast cancer, radiotherapy, chemotherapy, innate immunity, adaptive immunity
- MeSH terms
- Animals, Antineoplastic Agents, Bone Neoplasms, Colonic Neoplasms, Disease Models, Animal, Humans, Mice, Inbred BALB C, Neoplasms, Organoplatinum Compounds, Pyridines, Osteosarcoma, Cell Line, Tumor, Toll-Like Receptor 4, Mice
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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.
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