Knockdown of HMGB1 inhibits the crosstalk between oral squamous cell carcinoma cells and tumor-associated macrophages

Jinlin Wen; Panpan Yin; Ying Su; Feng Gao; Yanlin Wu; Wenbin Zhang; Peng Chi; Jiahui Chen; Xinyan Zhang

doi:10.1016/j.intimp.2023.110259

Knockdown of HMGB1 inhibits the crosstalk between oral squamous cell carcinoma cells and tumor-associated macrophages

Int Immunopharmacol. 2023 Jun:119:110259. doi: 10.1016/j.intimp.2023.110259. Epub 2023 May 2.

Authors

Jinlin Wen¹, Panpan Yin¹, Ying Su¹, Feng Gao¹, Yanlin Wu¹, Wenbin Zhang¹, Peng Chi¹, Jiahui Chen¹, Xinyan Zhang²

Affiliations

¹ Beijing Institute of Dental Research, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, 100050, China.
² Beijing Institute of Dental Research, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing, 100050, China. Electronic address: xinyanzhangzh@126.com.

PMID: 37141670
DOI: 10.1016/j.intimp.2023.110259

Abstract

Tumor-associated macrophages (TAMs), the major component of the tumor microenvironment (TME), play distinctly different roles in different tumors. High mobility group box 1 (HMGB1), a nonhistone protein in the nucleus, can perform functions during inflammation and cancers. However, the role of HMGB1 in the crosstalk between oral squamous cell carcinoma (OSCC) cells and TAMs remains unclear. Here, we established a coculture system of TAMs and OSCC cells to explore the bidirectional effect and potential mechanism of HMGB1 in OSCC cell-TAM interactions. Our results showed that HMGB1 was significantly upregulated in OSCC tissues and positively associated with tumor progression, immune cell infiltration and macrophage polarization. Then, knocking down HMGB1 in OSCC cells inhibited the recruitment and polarization of cocultured TAMs. Moreover, the knockdown of HMGB1 in macrophages not only suppressed polarization, but also inhibited cocultured OSCC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, macrophages secreted higher levels of HMGB1 than OSCC cells, and dampening endogenous HMGB1 reduced HMGB1 secretion. Both OSCC cell-generated and macrophage-endogenous HMGB1 may regulate TAM polarization by promoting receptor TLR4 expression and NF-κB/p65 activation and enhancing IL-10/TGF-β expression. HMGB1 in OSCC cells may regulate macrophage recruitment via IL-6/STAT3. In addition, TAM-derived HMGB1 may affect aggressive phenotypes of cocultured OSCC cells by regulating the immunosuppressive microenvironment through the IL-6/STAT3/PD-L1 and IL-6/NF-κB/MMP-9 pathways. In conclusion, HMGB1 may regulate the crosstalk between OSCC cells and TAMs, including modulating macrophage polarization and attraction, enhancing cytokine secretion, and remodeling and creating an immunosuppressive TME to further affect OSCC progression.

Keywords: Crosstalk; HMGB1; Metastasis; OSCC; TAMs; TME.

MeSH terms

Cell Line, Tumor
HMGB1 Protein* / genetics
Humans
Interleukin-6
Mouth Neoplasms* / genetics
Mouth Neoplasms* / metabolism
Mouth Neoplasms* / pathology
NF-kappa B / metabolism
Squamous Cell Carcinoma of Head and Neck* / genetics
Squamous Cell Carcinoma of Head and Neck* / metabolism
Squamous Cell Carcinoma of Head and Neck* / pathology
Tumor Microenvironment
Tumor-Associated Macrophages / metabolism

Substances

HMGB1 Protein
Interleukin-6
NF-kappa B
HMGB1 protein, human