HMGB1 Signaling-Mediated Tumor Immunity in Cancer Progress

Tumor immunity is a cycle that begins with the release of antigens from tumor cells and ends with the destruction of tumor cells. High mobility group box 1 (HMGB1) is a nonhistone protein widely present in the nucleus of mammalian cells and can be released by immune cells or tumor cells. As a proinflammatory mediator or alarm protein, the activity and function of HMGB1 are determined by the environment, binding receptors, redox status and posttranslational modifications (PTMs), and HMGB1 plays a key role in inflammation and tumor immune processes. In this review, we summarize in detail the current studies on the dual role of HMGB1 in tumor immunity, focusing mainly on immunosuppressive effects, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), as well as antitumor immunoenhancement effects, such as immunogenic cell death (ICD). Finally, we discuss the potential and challenges of HMGB1 in antitumor immunotherapy.

Keywords

HMGB1

tumor immunity

MDSCs

Tregs

TAMs

ICD

Funding

7202057/Beijing (China) municipal Natural Science Foundation

81772868/China National Nature Science Foundation

Figures

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Fig. 1.

Schematic illustration of the dual role of HMGB1 in tumor immunity drawn by Figdraw. In the TME, HMGB1 can exert an immunosuppressive role by regulating the proliferation, activation and survival of MDSCs, the differentiation and activation of Tregs, and the polarization and recruitment of TAMs. On the other hand, HMGB1 can also enhance antitumor immune responses by inducing ICD. Specifically, first, secreted HMGB1 induces MDSC differentiation from BM progenitor cells, increases MDSC proliferation by promoting IL-17 secretion by binding to the receptors RAGE or TLR4, enhances MDSC development by activating nuclear factor- $\kappa{}$ B (NF- $\kappa{}$ B) signaling, and promotes MDSC survival by regulating autophagy. Second, HMGB1 can promote the differentiation and activation of Tregs. Third, HMGB1 may promote M1 polarization of TAMs by binding to receptors the TLR4 or RAGE to activate NF- $\kappa{}$ B signaling, contribute to M2 polarization by binding to the receptors RAGE or TLR2 or by the secretion of IL-10/transforming growth factor- $\beta{}$ (TGF- $\beta{}$ ), and enhance macrophage recruitment by IL-6/STAT3 signaling. Finally, HMGB1 may mature DCs by TLR4/MyD88, RAGE/MAPK/NF- $\kappa{}$ B or STAT3 signaling to further induce ICD.

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Front. Biosci. (Landmark Ed) Print ISSN 2768-6701 Electronic ISSN 2768-6698