Head and neck cancers affect the lips, oral cavity, oropharynx, nasopharynx, hypopharynx and larynx, and >836,000 new cases and 431,000 related deaths occur each year worldwide (1). Head and neck squamous cell carcinoma (HNSCC), an aggressive malignancy characterized by relatively high rates of local recurrence, low responsiveness to therapy and lymph node metastasis (2), comprises ≤90% of head and neck cancers (3). Although notable progress has been made over the past few decades in surgical, chemotherapeutic and tumor-targeting therapies for HNSCC, patient prognosis remains unsatisfactory (4). To date, the epidermal growth factor receptor-targeting biological factor cetuximab, is the only Food and Drug Administration-approved targeted therapy for HNSCC (5). However, combinatorial cetuximab treatment with radiation or chemotherapy provides only a modest benefit to survival time (29.3 vs. 49 months and 7.4 vs. 10.1 months, respectively) (6,7). Furthermore, in clinical trials, cetuximab resistance was frequently observed, along with c-mesenchymal-epithelial transition (Met) activation (8–11). Aberrant hepatocyte growth factor (HGF)/c-Met signaling has been frequently reported in HNSCC (11–14); HGF-induced Met activation is a known mechanism of cetuximab resistance (15). Therefore, given its role in HNSCC, the HGF/Met pathway may serve as a potential target for treatment of HNSCC.

Met is a transmembrane tyrosine kinase receptor (RTK) of HGF (16,17), which is structurally distinct from most other RTKs. Met consists of a 45 kDa extracellular α-chain and a 145 kDa transmembrane β-chain (18). Following binding of HGF, two Met receptors dimerize, thereby leading to phosphorylation of tyrosine residues and subsequent activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), Wnt/β-catenin, Ras/Raf and signal transducer and activator of transcription 3 pathways (19–23). By activating these pathways, HGF/Met signaling serves important physiological roles in several biological processes, including embryogenesis, wound healing and tissue regeneration (24–27). However, during carcinogenesis, these functions promote tumor development, progression, metastasis and angiogenesis in several malignant tumors, including HNSCC (27,28). Although the HGF/Met pathway and HGF and/or Met inhibitors have been extensively studied (29–33), their roles in tumor immunity remain elusive. The present review article summarizes the current body of knowledge on HGF/Met signaling in HNSCC, including the association between gene and protein alterations, biological functions and patient outcomes. In addition, this article examines the roles of the HGF/Met signaling in tumor immunity and highlights the association between the expression of HGF/Met and prognosis of patients with HNSCC from the perspective of tumor immunity.

The immune system serves an essential role in the development of tumors (72,73). Data obtained from the Tumor Immune Estimation Resource database suggested that HGF expression was significantly positively correlated with the infiltration levels of the majority of the immune cells, including B cells, T cells, macrophages, neutrophils and dendritic cells (DCs) (74,75). This finding is consistent with the chemotactic function of HGF, but not MET, and is discussed in detail below (Fig. 1D). The HGF/Met signaling pathway has been implicated in immuno-inflammation and the modulation of immune cell functions (Fig. 2) (76). It has been shown that HGF and MET are expressed in activated B cells but not in naïve B cells (77). Therefore, HGF/Met enhances B cell adhesion, migration, growth, development, survival and antibody production via mechanisms involving nuclear factor-κB and ras-related C3 botulinum toxin substrate 1 (77–83). A recent study demonstrated that tumor-infiltrating B cells may recruit CD8⁺ T cells via CXC motif chemokine ligand 9 and maintain CD8⁺ T cell survival in HNSCC (84). Furthermore, MET is strongly expressed in thymocytes, particularly in the CD4⁺ CD8⁺ double-positive subset; however, it is barely detectable in stromal cells (85). Emerging evidence has shown that HGF/Met signaling is critical for T cell lymphopoiesis, development and maturation, as well as thymocyte chemotaxis (76,77).

Neutrophils contain pro-HGF in secretory granules that can be cleaved, activated and released; therefore, de novo protein synthesis is not required upon cell stimulation (86). It has been reported that the treatment of chemotherapy-induced neutropenia using granulocyte-colony-stimulating factor, results in a significant increase in plasma HGF levels (87). HGF has been shown to promote the adhesion and migration of neutrophils (88). The HGF/Met axis has both pro- and anti-tumor effects in neutrophils. Neutrophil infiltration is considered as a predictor of poor prognosis in patients with bronchioloalveolar carcinoma (89). In addition, tumor neutrophils actively enhanced hepatocellular carcinoma cell metastasis both in vitro and in vivo via interactions with HGF/c-Met (90). However, in a murine model, conditional deletion of Met in neutrophils increased tumor growth and metastasis, whereas Met was also shown to be required for the recruitment of anti-tumor neutrophils (91).

Tumor-associated macrophages are involved in cancer progression and metastasis (92). HGF attenuated lipopolysaccharide-induced IL-6 production and promoted IL-10 production in macrophages, thereby reducing inflammation (87,93). Furthermore, HGF has been implicated in the recruitment of monocyte/macrophages to injured tissues and the promotion of tissue repair (94). Although HGF inhibits the differentiation of inflammatory macrophages and promotes the differentiation of anti-inflammatory macrophages, which in turn may promote HSNCC progression, the influx of monocytes, which initiates the immune response, may also inhibit HNSCC tumorigenesis (92).

DCs serve key roles in both innate and adaptive immune responses (95,96), and several studies have shown that HGF/Met signaling promotes the adhesion and migration of DCs (97,98). However, the effect of HGF on the antigen-presenting ability of DCs remains controversial. Benkhoucha et al (99) and other studies (77,97) demonstrated that neither HGF nor ablation of MET affects the ability of DCs to present antigenic peptides to CD4⁺ T cells and induce the expansion of regulatory T cells. In contrast, another study using a murine model showed that HGF inhibited antigen presentation by DCs (100). Additionally, PI3K-dependent activation of Met upregulated PD-L1 expression in renal, gastric, liver and non-small cell lung cancer cells (101–104). However, the PI3K pathway is often mutated and activated in HNSCC (105). Increased Met expression was significantly associated with decreased PD-L1 expression (P=0.010) in HNSCC (67), indicating that there may be another regulatory mechanism between Met and PD-L1 in HNSCC, and combined blockade of Met and PD-L1 could exert mutually reinforcing effects.

In summary, it is hypothesized that the positive correlation between the expression of HGF and immune cell infiltration in HNSCC may be associated with the inhibition of tumorigenesis and may support the notion that HGF overexpression predicts increased OS. However, additional evidence is required to support this hypothesis. Therefore, it is hypothesized that targeting Met and particularly HGF for treatment of HNSCC may compromise several functions of anti-tumor immune cells. Thus, clinical trials using HGF or Met inhibitors for HNSCC therapy should be cautiously evaluated.

Due to its crucial role in cancer cell proliferation, invasion and metastasis, HGF/Met signaling is an attractive target for the treatment of HNSCC. The present review summarizes the current body of knowledge of the role of HGF/Met signaling in HNSCC, including gene and protein alterations, biological functions, patient outcomes and tumor-immune system interactions. Given that patients with tumors exhibiting high-level MET amplification or MET exon 14-skipping variants are more likely to benefit from anti-Met therapies (29), the detection of MET alterations is necessary for assessing whether to use Met inhibitors to treat HNSCC. Several researchers have hypothesized that HGF is a promising therapeutic target for HNSCC treatment. However, given the impact of the HGF/Met signaling in the recruitment of immune cells, the association between the expression of HGF and HNSCC outcomes, and the early termination of a phase III study combining an HGF antibody (rilotumumab) with chemotherapy due to the increased number of deaths in the rilotumumab arm vs. that in the placebo arm (106), it is hypothesized that inhibition of HGF could attenuate several anti-tumor immune responses. Therefore, intratumoral administration of HGF inhibitors may not be a suitable approach for the treatment of HNSCC. Ultimately, a clinical approach that may improve the efficacy of Met therapy for HNSCC, namely, intratumoral administration of Met inhibitors in order to reduce the inhibitory effect on immune cell recruitment may instead improve patient outcomes. However, further studies are required to provide an improved understanding of the effects of the HGF/Met pathway on the tumor microenvironment and to evaluate the therapeutic value of targeting HGF/Met in HNSCC. In addition, given the important role of HGF/Met signaling on immune cells, it is necessary to study the effects of HGF and Met inhibitors on immune cells in the tumor environment; however, to the best of our knowledge, no studies have assessed this at present. Therefore, the effects of HGF and Met inhibitors on immune cells in the tumor environment should be the focus of future studies and clinical trials using HGF or Met inhibitors for HNSCC therapy should be cautiously evaluated.