The tumor ecosystem in head and neck squamous cell carcinoma and advances in ecotherapy

Abstract

The development of head and neck squamous cell carcinoma (HNSCC) is a multi-step process, and its survival depends on a complex tumor ecosystem, which not only promotes tumor growth but also helps to protect tumor cells from immune surveillance. With the advances of existing technologies and emerging models for ecosystem research, the evidence for cell-cell interplay is increasing. Herein, we discuss the recent advances in understanding the interaction between tumor cells, the major components of the HNSCC tumor ecosystem, and summarize the mechanisms of how biological and abiotic factors affect the tumor ecosystem. In addition, we review the emerging ecological treatment strategy for HNSCC based on existing studies.

Keywords: Ecological therapy; Head and neck squamous cell carcinoma; Tumor ecosystem.

Fig. 1

Tumor ecosystem in HNSCC. The tumor is a complex ecosystem composed of various cell types and microorganisms (e.g., HPV and bacterium). Besides biological factors, ECM, energy, oxygen, and therapeutic interventions (e.g., radiation) serve as abiotic factors that also shape the tumor ecosystem. Abbreviations: CAF, cancer-associated fibroblast; DC, dendritic cell; ECM, extracellular matrix; HPV, human papillomavirus; HNSCC, head and neck squamous cell carcinoma; MDSC, myeloid-derived suppressor cell; NK, natural killer; TAM, tumor-associated macrophage

Fig. 2

Crosstalk between CAFs and tumor cells in the tumor ecosystem. CAFs can mediate tumor progression and transformation by interacting with tumor cells through secreting multiple chemokines, cytokines, and other effector molecules such as IL-1β, MMP2, EREG. Notably, CAFs can be activated by tumor cells through signals including IL-1β. Abbreviations: BDNF, brain-derived neurotrophic factor; CAF, cancer-associated fibroblast; CCL2, C–C chemokine ligand 2; CSC, cancer stem cell; CXCL12, C-X-C chemokine ligand 12; CXCR2, C-X-C motif chemokine receptor 2; ECM, extracellular matrix; Gal-1, galectin-1; HAS2, hyaluronan synthase 2; EREG, epiregulin; HGF, hepatocyte growth factor; IL-1β, interleukin-1β; JAK2-STAT3, janus kinase 2-signal transducer and activator of transcription 3; MAPK/AKT, mitogen-activated protein kinase/ protein kinase B; MCP-1, monocyte chemoattractant protein-1; c-Met, cellular-mesenchymal epithelial transition factor; MFAP5, microfibrillar associated protein 5; MMP2, matrix metalloproteinase 2; PTK7, protein tyrosine kinase 7; SOX9, sex determining region Y box 9; TGF-β, transforming growth factor-beta; TIMP1, tissue inhibitor matrix metalloproteinase 1

Fig. 3

Overview of protumor effects of TAMs in head and neck squamous cell carcinoma. TAMs promote tumor progression by participating in tumor invasion, metastasis, and angiogenesis as well as immunosuppression. Abbreviations: CCL2, C–C chemokine ligand 2; CCR2, CC chemokine receptor 2; ECM, extracellular matrix; HLA-G, human leucocyte antigen-G; IL-6, interleukin-6; MMP9, matrix metalloproteinase 9; PD-L1, programmed death-ligand 1; TAM, tumor-associated macrophage; TGF-β, transforming growth factor-beta; VEGF, vascular endothelial growth factor

Fig. 4

Crosstalk between tumor cells and T cells. IL-23 and -6 secreted by tumor cells recruit Th17, whereas the ratio of Th17 and Tregs influence HNSCC progression. Abbreviations: IL-6, interleukin-6; FGL1, fibrinogen-like protein 1; LAG-3, lymphocyte activated gene-3; PD-1, programmed cell death protein-1; PD-L1/2, programmed death-ligand 1/2; Th17, T helper 17; TIM-3, T cell immunoglobulin mucin-3