The TIM-3 receptor on dendritic cells inhibits nucleic acid–stimulated antitumor immunity.
Major finding: The TIM-3 receptor on dendritic cells inhibits nucleic acid–stimulated antitumor immunity.
Mechanism: TIM-3 binding to HMGB1 prevents nucleic acid trafficking necessary for innate immune signaling.
Impact: Targeting of TIM-3 may improve patient responses to cytotoxic chemotherapies.
Dendritic cells (DC) are critical components of the innate immune system that are stimulated in response to pathogens and stressors, including tumor-derived factors. Nucleic acids, such as those released by dying cells, activate Toll-like receptors (TLR) on DCs and initiate immune responses that are in part mediated by high-mobility group box 1 (HMGB1) protein. Chiba and colleagues examined the mechanisms of how tumor-associated DCs regulate cancer immunity, in particular the role of the receptor T-cell immunoglobulin mucin 3 (TIM-3). Elevated TIM-3 expression was detected on tumor-associated DCs (TADC) within the microenvironment of mouse and human tumors. Expression of this receptor reduced cytokine production induced by TLR agonists or synthetic DNA, whereas inhibition of TIM-3 with the use of a monoclonal antibody enhanced cytokine levels in TADCs, suggesting that DC-derived TIM-3 suppresses nucleic acid–stimulated antitumor responses. In support of this idea, DC depletion or TIM-3 blockade enhanced the ability of DNA vaccination to inhibit tumor growth, and this protective effect was dependent on type I IFN and interleukin-12 signaling induced by DNA. Furthermore, TIM-3 impaired chemotherapy-triggered immunogenic cell death, as TIM-3 blockade synergized with cisplatin to augment cytokine production stimulated by dying tumor cells in vitro and significantly reduced tumor growth in vivo. TIM-3 attenuation of chemotherapeutic efficacy required the presence of functional DCs and HMGB1 detection of nucleic acids. Specifically, TIM-3 inhibited innate immune responses by competing with DNA for binding to the A-box domain of HMGB1, thereby preventing the HMGB1-mediated recruitment of DNA into endosomes that is required for innate immune signaling. Taken together, these results identify a mechanism by which TADCs negatively regulate chemotherapy-induced antitumor immune responses and suggest that TIM-3 inhibition may be useful in treating patients who do not respond to cytotoxic chemotherapy drugs.
Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, et al. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol 2012 July 29 [Epub ahead of print].
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