Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1

Chiba, Shigeki; Baghdadi, Muhammad; Akiba, Hisaya; Yoshiyama, Hironori; Kinoshita, Ichiro; Dosaka‐Akita, Hirotoshi; Fujioka, Yoichiro; Ohba, Yusuke; Gorman, Jacob V.; Colgan, John; Hirashima, Mitsuomi; Uede, Toshimitsu; Takaoka, Akinori; Yagita, Hideo; Jinushi, Masahisa

doi:10.1038/ni.2376

Cited by 654 publications

(623 citation statements)

References 50 publications

Supporting

Mentioning

610

Contrasting

Unclassified

Order By: Relevance

“…30 HMGB1 initiates potent inflammation by stimulating the production of proinflammatory cytokines 52 from APCs via its binding to different surface receptors including receptor for advanced glycation end-products (RAGE), TLR2, TLR4, TLR9, and TIM3 ( Figure 1). 53,54 Importantly, the binding of HMGB1 to TLR4 on APCs was required to suppress tumor development, which is consistent with clinical study showing that breast cancer patients harboring a single-nucleotide polymorphism (Asp299Gly) in the TLR4 gene undergo an early relapse after anthracycline treatment. 30,55,56 In contrast, secreted HMGB1 could induce a protumor inflammation to facilitate tumor progression.…”

Section: Hmgb1supporting

confidence: 81%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

View full text Add to dashboard Cite

Apoptotic cell death generally characterized by a morphologically homogenous entity has been considered to be essentially non-immunogenic. However, apoptotic cancer cell death, also known as type 1 programmed cell death (PCD), was recently found to be immunogenic after treatment with several chemotherapeutic agents and oncolytic viruses through the emission of various danger-associated molecular patterns (DAMPs). Extensive studies have revealed that two different types of immunogenic cell death (ICD) inducers, recently classified by their distinct actions in endoplasmic reticulum (ER) stress, can reinitiate immune responses suppressed by the tumor microenvironment. Indeed, recent clinical studies have shown that several immunotherapeutic modalities including therapeutic cancer vaccines and oncolytic viruses, but not conventional chemotherapies, culminate in beneficial outcomes, probably because of their different mechanisms of ICD induction. Furthermore, interests in PCD of cancer cells have shifted from its classical form to novel forms involving autophagic cell death (ACD), programmed necrotic cell death (necroptosis), and pyroptosis, some of which entail immunogenicity after anticancer treatments. In this review, we provide a brief outline of the well-characterized DAMPs such as calreticulin (CRT) exposure, high-mobility group protein B1 (HMGB1), and adenosine triphosphate (ATP) release, which are induced by the morphologically distinct types of cell death. In the latter part, our review focuses on how emerging oncolytic viruses induce different forms of cell death and the combinations of oncolytic virotherapies with further immunomodulation by cyclophosphamide and other immunotherapeutic modalities foster dendritic cell (DC)-mediated induction of antitumor immunity. Accordingly, it is increasingly important to fully understand how and which ICD inducers cause multimodal ICD, which should aid the design of reasonably multifaceted anticancer modalities to maximize ICD-triggered antitumor immunity and eliminate residual or metastasized tumors while sparing autoimmune diseases.

show abstract

Section: Hmgb1supporting

confidence: 81%

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

2013

View full text Add to dashboard Cite

show abstract

“…[215][216][217][218][219][220][221] Moreover, HMGB1 binds not only to TLR2, TLR4 and RAGE, but also to hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3), hence mediating immunosuppressive (as opposed to immunostimulatory) effects. [222][223][224] Taken together, these observations suggest that the biological activity of HMGB1 exhibits a consistent degree of contextdependency. Nonetheless, HMGB1-deficient malignant cells exposed to ICD inducers fail to elicit adaptive immune responses upon inoculation into immunocompetent syngeneic mice, a defect that can be corrected by the co-administration of synthetic TLR4 ligands.…”

Section: Immunogenic Cell Death Signalingmentioning

confidence: 64%

Consensus guidelines for the detection of immunogenic cell death

et al. 2014

View full text Add to dashboard Cite

“…35,36 In the cytoplasm, HMGBs bind immunogenic nucleotides and deliver them to the cytosolic nucleic acid sensors retinoic acid-inducible gene I, MDA5, AIM2 and DAI and to the endosome nucleic acid-sensing TLRs (TLR3, TLR7 and TLR9). 7,10 Reports have also highlighted the interactions of HMGB1 with TLR9, retinoic acid-inducible gene I and TIM-3 10,37,38 and the vital role of HMGBs in autophagy regulation, 39 mitochondrial function and morphology [40][41][42] and cell proliferation. [43][44][45] Comparatively, an understanding of HMGBs in the nucleus is limited.…”

Section: Discussionmentioning

confidence: 99%

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Rao

Yang

et al. 2014

Cell Mol Immunol

View full text Add to dashboard Cite

High-mobility group box (HMGB) proteins, a family of chromatin-associated nuclear proteins, play amazingly multifaceted roles in the immune system of mammals. Thus far, little is known about the nucleocytoplasmic distribution of HMGBs in teleosts. The present study systematically investigated the dynamic localization of all six HMGB proteins in Ctenopharyngodon idella kidney (CIK) cells. Under basal conditions, all HMGBs exclusively localized to the nucleus. Grass carp reovirus (GCRV), polyinosinic-polycytidylic (poly(I : C)) potassium salt and lipopolysaccharide (LPS) challenge evoked the nuclear export of HMGBs to various degrees: GCRV challenge induced the highest nuclear export of CiHMGB2b, and poly(I : C) and LPS evoked the highest nucleocytoplasmic shuttling of CiHMGB1b. Overall, the nucleocytoplasmic shuttling of CiHMGB2a and CiHMGB3b was rarely induced by these challenges. Dynamic imaging uncovered that the nucleocytoplasmic GCRV-induced relocation of CiHMGB2b occurred in cells undergoing karyotheca rupture, apoptosis or proliferation. Western blot analyses were used to examine HMGB-EGFP fusion proteins in whole cell lysates, cytosol, nuclear fractions and culture medium. Further investigation demonstrated the nuclear retention of N-terminal HMG-boxes and the nucleocytoplasmic distribution of the C-terminal acidic tails. Comparative analyses of the dynamic relocation of full-length, truncated or chimeric HMGBs confirmed that the intramolecular interaction between HMG-boxes and C-tail domains mediated the nucleocytoplasmic translocation of HMGBs. These results not only provide an overall understanding of the subcellular localization of HMGBs, but also reveal the induction mechanism of the nucleocytoplasmic translocation of HMGBs by GCRV challenge, which lays a foundation for further studies on the interactions among pathogens, HMGBs and pattern recognition receptors in the innate immunity of teleosts. Keywords: grass carp (Ctenopharyngodon idella); grass carp reovirus; HMGBs; innate immunity; subcellular localization INTRODUCTION High-mobility group box (HMGB) proteins are abundant non-histone chromatin components implicated in major DNA transactions. In mammals, there are four family members (HMGB1-4), of which HMGB1, 2 and 3 are characterized by two DNA-binding domains (HMG-box A and B) and a Cterminal acidic tail domain and HMGB4 possesses two HMG-boxes but lacks the acidic tail. 1 In some teleosts, such as fugu (Takifugu), medaka (Oryzias latipes), Tetraodon and stickleback, two paralogous genes were detected for HMGB1 and HMGB2 but not for HMGB3. 2 However, in zebrafish (Danio rerio), salmon (Oncorhynchus), carp (Cyprinus carpio) 2 and grass carp (Ctenopharyngodon idella), 3-5 two paralogs are present within each of the HMGB subfamilies (HMGB1,

show abstract

Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1

Cited by 654 publications

References 50 publications

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

Consensus guidelines for the detection of immunogenic cell death

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

Contact Info

Product

Resources

About