Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1
By S. Chiba, Muhammad Baghdadi, H. Akiba, H. Yoshiyama, I. Kinoshita, H. Dosaka-akita, Y. Fujioka, Y. Ohba, Jacob V. Gorman, J. Colgan and 5 more. Nature Immunology, 2012
783 citations recorded by the source corpus.
The mechanisms by which tumor microenvironments modulate nucleic acid–mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.
Subfields: Immunology
View Paper: https://www.semanticscholar.org/paper/6bf7c2661d1bd9c127e427fa8e21e7f753dd5ba9
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In Immunology
Citations in the corpus
- Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer (2016, positive): “Other studies suggest more complex actions of TIMs; for example, TIM-3 expressed on tumor-associated DCs suppressed TLR-mediated innate immune responses to nucleic acids by interfering with HMGB1-mediated anti-tumor immunesurveillance mechanisms.(63) Although these studies provide significant insigh”
- Dendritic Cells and Cancer Immunity (2016, background): “Interestingly, CD11c+ myeloid cell activation within tumors may be limited by binding of HMGB1 to T-cell immunoglobulin and mucin-domain containing (TIM)-3, although this receptor impacts tumor growth independently of a T cell response and therefore the role of this pathway in regulating cDC activit”
- Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 (2019, background): “In tumor, TIM-3 was highly expressed on tumor infiltrating DCs and can compete with nucleic acid binding to HMGB1, therefore dampening anti-tumor immunity mediated by nucleic acids [87].”
- Immunogenic cell death and DAMPs in cancer therapy (2012, background): “These authors showed that a recombinant N-terminal fragment of CRT (39-272) is a potent inducer of activation and maturation of B cells and macrophages and can trigger Ig class switching in B cells without T cell help in vitro and in vivo72.”