High Mobility Group Box 1 (HMGB1) Induces Toll-Like Receptor 4-Mediated Production of the Immunosuppressive Protein Galectin-9 in Human Cancer Cells

Abstract

High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in the cell nucleus. However, stressed, dying, injured or dead cells can release this protein into the extracellular matrix passively. In addition, HMGB1 release was observed in cancer and immune cells where this process can be triggered by various endogenous as well as exogenous stimuli. Importantly, released HMGB1 acts as a so-called “danger signal” and could impact on the ability of cancer cells to escape host immune surveillance. However, the molecular mechanisms underlying the functional role of HMGB1 in determining the capability of human cancer cells to evade immune attack remain unclear. Here we report that the involvement of HMGB1 in anti-cancer immune evasion is determined by Toll-like receptor (TLR) 4, which recognises HMGB1 as a ligand. We found that HGMB1 induces TLR4-mediated production of transforming growth factor beta type 1 (TGF-β), displaying autocrine/paracrine activities. TGF-β induces production of the immunosuppressive protein galectin-9 in cancer cells. In TLR4-positive cancer cells, HMGB1 triggers the formation of an autocrine loop which induces galectin-9 expression. In malignant cells lacking TLR4, the same effect could be triggered by HMGB1 indirectly through TLR4-expressing myeloid cells present in the tumour microenvironment (e. g. tumour-associated macrophages).

Expression of the Immune Checkpoint Protein VISTA Is Differentially Regulated by the TGF-β1 – Smad3 Signaling Pathway in Rapidly Proliferating Human Cells and T Lymphocytes

“…We used the THP-1 cell line (monocytic leukemia) and more premature primary human acute myeloid leukemia (AML) blasts. In THP-1 cells, TGF-β is known to highly upregulate galectin-9 expression in a Smad3-dependent manner (a significant increase in Smad3 phosphorylation induced by TGF-β was also reported for these cells) (3,20). Furthermore, THP-1 cells do not express detectable amounts of granzyme B protein and do not show detectable catalytic activity of this enzyme (9).…”

“…With monocytic AML cells, which do not express detectable amounts of granzyme B protein ( 9 ), this biological response has probably more complex reasons. THP-1 cells secrete high levels of galectin-9, especially when pre-treated with PMA or other triggers of exocytosis (such as latrotoxin, or Toll-like receptor (TLR) ligands) ( 20 ). They are also capable of secreting VISTA.…”

Tumor metastasis: Mechanistic insights and therapeutic interventions

“…In the early stage of metastasis, autophagy mainly suppresses the occurrence of metastasis by regulating the anti‐tumor immune response. 213 , 214 , 215 Autophagy‐related protein 5(ATG5) is considered to be closely related to autophagy. In pancreatic ductal adenocarcinoma, mice with ATG5 knockout developed more tumors and metastases than control mice.…”

“… 214 In addition, studies have found that autophagy can stimulate tumor‐related spontaneous inflammation by releasing high mobility group box 1 and enhance the antitumor immune response of DCs to limit metastasis. 215 In the later stage of tumor metastasis, autophagy reduces the adhesion between tumor cells and ECM by regulating the activity of the Rho family so as to promote tumor migration and invasion. 216 In addition, autophagy can enhance tumor invasion and promote the progress of tumor metastasis by inhibiting anoikis of CTCs, maintaining the stemness of CSCs, and reawakening dormant tumor cells.…”

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

“…Therefore, we speculated that the inhibition role of MS19 on HMGB1 secretion is partially mediated through NF-κB signaling and TNF-α-dependent mechanism, since that ODN exhibited a strong inhibition against the NF-κB activation and TNF-α production in this study. In addition, after its release, extracellular HMGB1 usually acts as a DAMP molecule and transmits signals to the cell interior via the activation of receptors including TLR4, resulting in the formation of a positive feedback loop that potentially amplifies local inflammatory responses ( Su et al, 2021 ; Teo Hansen Selno et al, 2021 ). Thus, MS19 might also interact with the secreted HMGB1, leading to the functional inactivation by the induction of a conformational change.…”