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Yousuf, P. Head and Neck Tumor Microenvironment. Encyclopedia. Available online: https://encyclopedia.pub/entry/9407 (accessed on 24 December 2025).
Yousuf P. Head and Neck Tumor Microenvironment. Encyclopedia. Available at: https://encyclopedia.pub/entry/9407. Accessed December 24, 2025.
Yousuf, Parvaiz. "Head and Neck Tumor Microenvironment" Encyclopedia, https://encyclopedia.pub/entry/9407 (accessed December 24, 2025).
Yousuf, P. (2021, May 08). Head and Neck Tumor Microenvironment. In Encyclopedia. https://encyclopedia.pub/entry/9407
Yousuf, Parvaiz. "Head and Neck Tumor Microenvironment." Encyclopedia. Web. 08 May, 2021.
Head and Neck Tumor Microenvironment
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22094584

Head and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations in the cellular and non-cellular components of the HNSCC tumor micro-environment (TME) play a critical role in regulating many hallmarks of cancer development including evasion of apoptosis, activation of invasion, metastasis, angiogenesis, response to therapy, immune escape mechanisms, deregulation of energetics, and therefore the development of an overall aggressive HNSCC phenotype. Cytokines and chemokines are small secretory proteins produced by neoplastic or stromal cells, controlling complex and dynamic cell–cell interactions in the TME to regulate many cancer hallmarks. 

head and neck squamous cell carcinomas cytokines chemokines tumor microenvironment apoptosis invasion metastasis angiogenesis response to therapy immune evasion

1. Introduction

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a dismal prognosis. With an annual incidence of ~800,000 new cases and 350,000 deaths worldwide, HNSCC is the sixth most common cancer globally [1]. HNSCC includes tumors of the oral cavity, hypopharynx, oropharynx, larynx and, paranasal sinuses and is clinically, pathologically, phenotypically, and biologically a heterogeneous disease [2]. Oral squamous cell carcinoma (OSCC), being the primary subtype of HNSCC, accounts for two-thirds of the cases occurring in developing nations. Although tobacco and alcohol consumption account for nearly 75% of the total HNSCC cases, there has been a recent rise in the incidence of Human Papilloma Virus (HPV) associated oropharynx cancers (OPC) [3]. Cytokines and chemokines are soluble, low molecular weight secretory proteins, which regulate lymphoid tissue development, immune and inflammatory responses by controlling immune cell growth, differentiation, and activation [4][5]. While the cytokines are non-structural, pleiotropic proteins or glycoproteins, which have a complex regulatory influence on inflammation and immunity, chemokines are a large family of low molecular weight (8–14 KDa) heparin-binding chemotactic cytokines that regulate leukocyte trafficking, development, angiogenesis, and hematopoiesis [4][5]. Based on the variations in the structural motif of the first two closely paired and highly conserved cysteine residues, chemokines are divided into CXC, CC, CX3C, and the C subfamilies. While the C subfamily has only two cysteine residues, CXC, CC, and CX3C have four cysteine residues [6]. The letter ‘‘L” followed by a number denotes a specific chemokine (e.g., CCL2 or CXCL8). The receptors are labeled by the letter R followed by the number (e.g., CCR2 or CXCR1) [7][8]. Based on the conserved glutamic acid-leucine-arginine “Glu-Leu-Arg” (ELR) motif at the NH2 terminus, the CXC chemokine family is further subdivided into ELR+ve and ELR−ve. The ELR+ve CXC chemokines are angiogenic and activate CXCR2 mediated signaling pathway in endothelial cells, while the ELR−ve CXC chemokines are angio-static and are potent chemo-attractants for mononuclear leukocytes [9][10][11]. Cytokines such as TNF (α and β), interleukin 1 family (IL-1α, IL-1β, IL-1 receptor antagonistic (IL-Ira) and IL-2, IL -6, IL-8, IL-10, IL-11, IL-12, IL-15, IL-16, IL -17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, interferon’s (α, β, and γ), TGFβ, are produced by various types of cell including mononuclear phagocytic cells, T-lymphocytes, B-lymphocytes, Langerhans cells, polymorph nuclear neutrophils (PMNs), and mast cells [12]. Based on their biological properties, these cytokines are classified into T-helper 1 (Th1), T-helper 2 (Th2), and T-helper 17 (Th17) [13]. While Th1 and Th2 cytokines stimulate cellular and humoral immune responses, Th17 cytokines are known to regulate inflammatory responses and autoimmunity [13].

2. HNSCC Tumor Microenvironment

The HNSCC TME is a heterogeneous complex of cellular and non-cellular components that dictate aberrant tissue function and promote the development of aggressive tumors [14]. While the non-cellular components include extracellular matrix (ECM) proteins and many physical and chemical parameters, cellular components of HNSCC TME includes immune cells such as T cells, B cells, natural killer cells (NK cells), langerhans cells, dendritic cells (DC), myeloid-derived suppressor cells (MDSCs), macrophages, tumor associated-platelets (TAPs), mast cells, adipocytes, neuroendocrine cells, blood lymphatic vascular cells, endothelial cells (EC), pericytes and cancer-associated fibroblasts (CAFs) [15]. In addition to providing intermediate metabolites and nutrients to the tumor cells, these stromal cells secrete a diverse array of cytokines, chemokines, and growth factors that support tumor growth, progression, metastasis [16], host immunosuppression [17], and promote the development of aggressive tumors [18] (Figure 1). However, dysfunctional T-cells, regulatory T cells (Tregs), MDSCs, impaired NK cell activity, and type 2 macrophages (M2) present in the HNSCC TME have an inverse function and promote tumor growth, metastasis, and resistance to therapy [19]. The immunosuppressive HNSCC TME is also facilitated by the downregulation of MHC molecules (human leukocyte antigen, HLA), inactivation of the antigen processing machinery (APM), and dysregulation of checkpoint proteins (reviewed in [20]). The important HNSCC-associated TME cells, cytokines, chemokines, and growth factors are discussed below.

Ijms 22 04584 g001 550

Figure 1. Chemokine and cytokine-mediated crosstalk in head and neck squamous cell carcinoma (HNSCC) tumor micro-environment (TME). Cytokines and chemokines secreted by a variety of stromal cells affect tumor cell growth, proliferation & metastasis in many ways. By inducing immune-suppressive TME, they promote immune evasion and metastasis. Many chemokines and cytokines help degrade extracellular matrix (ECM) proteins, induce angiogenesis, and thereby promote invasion and metastasis.

Cancer-associated Fibroblasts (CAFs) are the major cell type in the HNSCC and help maintain a favorable TME aiding tumorigenesis [21]. Though controversial, CAFs are believed to be generated from myofibroblasts, transformed cancer cells, epithelial cells via epithelial-mesenchymal transition (EMT), resting resident fibroblasts or pericytes via mesothelial-mesenchymal transition (MMT), endothelial cells via endothelial to mesenchymal transition (EndMT), adipocytes, and bone marrow-derived mesenchymal stem cells (MSCs) [22]. HNSCC CAF’s secrete a wide variety of cytokines (autocrine or paracrine in function) and tumor-promoting factors essential for inflammation, cell proliferation, tumor growth, invasion & metastasis, angiogenesis, cancer stem cell (CSC) maintenance, and resistance to therapy [23]. These include various cytokines, interleukins (ILs) such as IL-6, IL-17A, and IL-22, growth factors such as EGF, HGF, VEGF, chemokines such as C-X-C motif chemokine ligands (CXCLs), CXCL1, CXCL8, CXCL12 (SDF-1α), and CXCL14, and C-C motif chemokine ligands (CCLs), CCL2, CCL5 and CCL7 [24][25]. These factors promote ECM degradation and modulation by secreting matrix metalloproteins (MMPs) such as MMP-2 and MMP-9 for effective invasion and metastasis of tumor cells [26]. Endothelins (iso-peptides) produced by vascular epithelium upon binding to CAFs activate ADAM17 and trigger release of EGFR ligands such as amphiregulin and TGF-α [26]. These ligands activate EGFR signaling in HNSCC cells, upregulate COX-2 and stimulate the growth, invasion, and metastasis of HNSCC cells [27]. Although little is known about the interaction of CAF-tumor cells in HNSCC, poor overall survival (OS) of HNSCC patients has been associated with increased α-SMA expression regardless of the clinical stage [23]. All these findings ascertain the credibility of CAFs in promoting growth and thus can be useful in facilitating the development of new therapeutic strategies against tumor progression in HNSCC.

Macrophages engage in both innate and adaptive immune responses and protect the body against invading pathogens. These macrophages can either help tumor growth or destroy tumor cells depending upon the external cues from TME. In response to interferons, macrophages are polarized and activated into pro-inflammatory classical M1 type that produces cytokines, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-23, IL-12, CCL5, CXCL9, CXCL10, and CXCL5 and help destroy tumor cells via activating Th1 cells [28]. M2 type macrophages closely resemble tumor-associated macrophages (TAMs) and are characterized by increased expression of IFN-γ, CCL2, CCL5, CXCL16, CXCL10, CXCL9, TNF-α, MMP9 and IL-10, arginase-1, and peroxisome proliferator-activated receptor-γ (PPAR-γ) [29]. HNSCC tumors with high M2 TAM infiltration have an advanced stage lymph node metastasis, and poor patient outcome [30]. Elevated CD68+ macrophages are also associated with poor patient survival [31]. Furthermore, increased M2 TAM infiltration is associated with increased tissue levels of macrophage migration inhibitory factor (MIF) and serum TGF-β levels. Though TGF-β is suppressive in function, MIF helps recruit neutrophils to the TME and promotes invasion and metastasis by producing ROS, MMP9 and, VEGF expression [32]. All these studies conclusively established the pro-tumorigenic role of M2 TAMs in regulating cell proliferation, invasion & metastasis, angiogenesis, and promoting immune evasion.

Neutrophils are the most abundant granulocytes present in the blood and an important component of innate and adaptive immunity by regulating T cell activation, antigen presentation and T cell-independent antibody responses [33]. Like TAMs, tumor-associated neutrophils (TANs) can be either tumor-promoting (N2) or tumor suppressors (N1). By activating platelets, neutrophils enhance the risk of cancer-associated venous thromboembolism (VTE) and death in HNSCC patients [34]. Due to the lack of specific markers, identification and characterization of TANs are difficult. However, nonspecific markers including CD14, CD15, CD16, CD11b, CD62L and CD66b are routinely used for their isolation and characterization (reviewed [30]). Natural Killer (NK) cells are large granular CD3−ve cytotoxic type 1 innate lymphoid cells that detect and kill virus-infected and cancer cells. Based on the expression of adhesion molecules CD56 and the low-affinity FcγR CD16, NK cells are classified into a highly cytotoxic CD56lowCD16high population predominantly present in the peripheral blood, and less cytotoxic CD56highCD16low cells present in the secondary lymphoid and other tissues [35]. These CD56highCD16low NK cells, like neutrophils and macrophages, kill cells directly by secreting a plethora of immunomodulatory molecules such as IL-5, IL-8, IL-10, IL-13, CCL2, CCL3, CCL4, CCL5 IFN-γ, TNF-α, GM-SCF and, CXCL10 [36]. Recently, tumor-infiltrating NK cells from HNSCC patients have been shown to possess a decreased expression of activating receptors like NKG2D, DNAM-1, NKp30, CD16, and 2B4 and upregulation of inhibitory receptors NKG2A and PD-1 compared to NK cells from matched peripheral cells [37]. The study also observed low cytotoxicity and reduced IFN-γ secretion from tumor-infiltrating NK cells in vitro [37]. Though no stimulation is needed for NK activation, a small percentage of NK T-cells (NKT) require priming for activation [38]. These NKT cells are specialized cells with morphological and functional characteristics and surface markers of both T and NK cells. The presence of another small subset of invariant NK T cells (iNKT) that express invariant αβ T cell receptors is associated with poor outcomes for HNSCC patients [39][40].

Myeloid-derived suppressor cells (MDSCs) are another class of inhibitory immune cells present in the TME of almost all solid tumors. MDSCs are a heterogeneous population of immature immune cells comprising early myeloid progenitors, immature dendritic cells (DCs), neutrophils, and monocytes, which negatively regulate the activity of NK cells and induce Tregs [41]. Though difficult to identify due to their diversity, MDSCs were initially identified from HNSCC patients as immature CD34+ cells [42][43]. MDSCs inhibit the production of innate inflammatory cytokines such as IL-23, IL-12, and IL-1 by DCs, thereby suppressing antitumor IFN-γ secreting CD4+ and CD8+ cytotoxic T cells [44]. They regulate T cell activation, migration, proliferation and induce apoptosis by overexpressing immunomodulatory cytokines like IL-10, TGF-β, CD86, PD-L1, TGF-β and suppressing IFN-γ production [45]. MDSCs indirectly suppress the T- cell activation by inducing Tregs, TAMs, and modulating NK cell activity. They also promote angiogenesis and metastasis by producing βFGF, TGF-β and, VEGFA and degrading ECM [46]. Therefore, targeting the inhibitory functions of MDSCs represents a novel avenue for therapeutic intervention in HNSCC tumors.

Regulatory T-cells are immunosuppressive cells with a crucial function in maintaining self-tolerance immune homeostasis (reviewed in [44]). They are also known to regulate CD4+ and CD8+ T cells, macrophages, B cells, NK cells, and DCs. Based on origin, localization, and marker expression, Tregs are mainly divided into CD25+ CD4+ Tregs (natural regulatory T cells) that mature in the thymus and peripheral CD25+ CD4+ Tregs (induced or adaptive Tregs). [47]. These Tregs are known to function by releasing IL-35, IL-10, and TGF-β, inhibiting DC maturation, cytolysis and granzyme/perforin dependent killing of cells, metabolic disruption of effector T cells, and modulation of DC maturation [48]. The genomic and epigenomic differences between HPV+ve and HPV−ve HNSCC tumors favor less infiltration of PD-1 and TIM3 co-expressing CD8+ T-cells in HPV−ve HNSCC [49]. On the contrary, HPV+ve HNSCC tumors are infiltrated with increased Tregs, Tregs/CD8+, and CD56low NK cells, CD56+ CD3+ NKT cells, CD3+ T cell, and activated T cells with increased CTLA4 and PD-1 expression and PD-1/TIM3 co-expressing CD8+ T cells, suggesting compromised immune system [50]. All these studies suggest heterogeneity in cellular phenotype, function, and location among HPV+ve and HPV−ve HNSCC tumors and may potentially be responsible for the varied therapeutic responses.

Besides Tregs, MDSCs, NK, macrophages, neutrophils, platelets, mast cells, adipose cells, and neuroendocrine cells constitute an integral part of the HNSCC TME. In addition to their thrombosis and wound healing activities, thrombocytes or platelets play an important role in tumor biology and inflammation. Besides the secretion of specific granules, viz. dense granules, lysosomes, and α-granules involved in platelet aggregation, platelets also secrete various growth factors in the TME [51]. Interestingly, these granules also contain membranous protein CD63 and lysosomal associated membrane protein 1 & 2 (LAMP1/2), integrin α2β3, p-selectin and glycoprotein-Iβ (GP-Iβ), and secrete molecules like ATP, ADP, Ca2+, serotonin, phosphatase into the TME [52]. It is interesting to mention that CD63 and LAMP1/2 membrane proteins help create an acidic environment for acid hydrolases’ optimum activity to degrade ECM [53]. Besides, α-granules also contain many growth factors, a wide variety of chemokines, MMPs, proteins like thrombospondin, fibrinogen, fibronectin, vitronectin, Von Willebrand factor (VWF), and inflammatory proteins that stimulate tumor growth and angiogenesis [54].

Mast cells are another critical component of the immune system regulating both innate and acquired immune response. When mast cells undergo cross-linkage with IgE receptor (FcERI) on their surface, mast cells exocytose many inflammatory mediators including histamine, heparin, prostaglandin D2 (PGD2), leukotriene C4 (LTC4), chondroitin sulfate E, chymase, tryptase, Cathepsin G, carboxypeptidase-A (CPA1), GM-CSF and interleukins into the TME [55]. These cells also secrete fibroblast growth factor-2 (FGF-2), VEGF, MMPs, protease, cytokines, chemokines, and promote proliferation, invasion, and migration of neoplastic cells and angiogenesis [56][57]. Mast cells produce numerous pro-angiogenic factors specific to HNSCC TME, such as FGFβ, TGFβ, tryptase, heparin, and MMPs, to support growth and development [58].In the HNSCC, increased mast cell numbers have been associated with angiogenesis and tumor progression [59].

Neuroendocrine cells release norepinephrine (NE) and epinephrine (E) neurotransmitters. They may either show strong antitumor properties or pro-tumorigenic effects by regulating tumor cell invasion and migration and modulating the immune response. Neurotransmitter substance P (SP) (a member of the tachykinin neuropeptide family), secreted by both tumor and stromal cells, is known to induce many cytokines (IL-1, IL-6, TNF-α). Neurotransmitter SP stimulates tumor cell migration and blocks the integrin β1 mediated adhesion of T cells [60]. In addition, SP also acts as a mitogen factor via a neurokinin-1 receptor (NK-1R), activates protein kinases (PK1 and 2), and promotes cell migration [61], proliferation and protection from apoptosis [62]. Interestingly, both SP and NK-1R are overexpressed and associated with the development and progression of HNSCC [63][64]. Secretion of NE neurotransmitters also inhibits TNF-α synthesis and thereby prevents the generation of CTLs [65]. The α- and β-adrenoreceptors (ARs) for NE and E are overexpressed in the HNSCC cell lines [66], and administration of NE has been shown to increase the proliferation of these cells [67]. A recent study has shown that increased expression of β2-AR promotes EMT in HNSCC cells by activating the IL-6/STAT3/Snail1 signaling pathway [68]. In addition, increased expression of β2-AR was associated with differentiation, lymph node metastasis, and reduced OS of HNSCC patients [68].

Dendritic cells are the most potent antigen-presenting cells (APCs). Through their interaction with lymphoid and myeloid cells, DCs play a vital role in regulating adaptive and innate immune responses during normal and pathophysiological conditions [69]. DCs become immunogenic upon maturation by up-regulation of MHC class II, co-stimulatory molecules, and by secretion of pro-inflammatory cytokines like IL-12, TNF-α, IL-1, and IL-6 [70]. Interestingly, tumor-associated or tumor-treated DCs show low levels of co-stimulatory molecules [71], slow production of IL-12, inhibited antigen-processing machinery (APM), suppressed endocytic activity, and abnormal motility, etc. [72][73]. While higher tumor infiltration of immature DCs is usually observed, increased immature DCs in patients’ peripheral blood with HNSCC, esophageal, lung, and breast cancer have also been reported [74]. Through abortive proliferation, anergy of CD4+ and CD8+ T lymphocytes or Tregs produce IL-10 and TGF-β and prevent immune response, immature DCs also induce tolerance, thus inhibiting co-stimulatory signals [75][76].

Endothelial cells (ECs) play an important role in the development and progression of many tumors [77]. By secreting large amounts of VEGF [78], ECs, in an autocrine manner, induce Bcl-2 expression in the TME micro-vessels and promote angiogenesis and tumor growth [79][80][81]. By regulating the secretion of various CXC chemokines in the HNSCC TME, Bcl-2 is known to enhance invasiveness and the development of recurrent tumors [82][83]. VEGF via IKK/IκB/NF-κB signaling pathway also modulates the expression levels of growth-related oncogene GRO-α (or CXCL1) and interleukin 8 (CXCL8) expression in HNSCC [79] and promotes the development of aggressive tumors. Another study reported that Jagged1, a notch ligand, induced by the growth factors via the activation of mitogen-activated protein kinase-activator protein-1 (MAPK) in HNSCC cells, triggered Notch signaling in adjacent endothelial cells, thus enhancing neovascularization and tumor growth in vivo [84]. Like the ECs, pericytes are an important cellular component of TME and critically important for tumor initiation, progression, and angiogenesis [85]. Pericytes and ECs communicate with each other by paracrine signaling or by chemo-mechanical signaling pathways [86]. By providing mechanical and physiological support to EC, pericytes stabilize vascular walls, promote vessel remodeling, maturation [87][88], regulation of blood flow, and vessel permeability [89]. Although, there are limited studies on the role of pericytes in HNSCC, some studies have shown the presence of abnormal vessels in the OSCC tumor tissue and a reduction of pericyte population in the peritumoral area, thus showing that the pericyte population is significantly affected during OSCC development [90][91][92].

Extracellular Matrix and Chemokine/Cytokine Activation

The ECM is a 3D network of interwoven macromolecules including glycoproteins, structural fibrous proteins (collagen, elastin, fibronectin, laminin, and tenascin), immersed with enzymes, growth factors, non-cellular components, physical and chemical parameters such as pH, oxygen tension, interstitial pressure, and fluid flux. The ECM provides biophysical, structural, mechanical, and biochemical support to the surrounding cells and helps in-cell adhesion, cell–cell communication, and differentiation [93][94]. Collagen, which constitutes about 30–40% of the total mass of ECM, plays a vital role in cell behavior regulation and development by providing mechanical and structural support and helps in cell adhesion, differentiation, migration, wound repair, and tissue scaffoldings [95][96]. Overexpression of type IV collagen is often observed in HNSCC [97], and collagen XVII, Col15 interaction with integrins has been shown to chemotactically attract HNSCC cells [98]. Notably, Type I collagen has been shown to stimulate the expression of IL-1α, IL-1β, IL-6, TNF-α, and TGF-β in HNSCC [99]. Glycoprotein fibronectin (Fn) produced by fibroblasts and endothelial cells interacts with fibrin, integrins, heparin, collagen, gelatin, and syndecan and promotes tumor progression, migration, invasion, and therapeutic resistance [100]. Peptide hydrolases and MMPs produced by tumor and stromal cells cleave the basement membrane, cell surface receptors, and adhesion molecules and result in the disorganization and deregulation of ECM necessary for invasion and metastasis [101][102]. As in many tumors, ECM proteins such as collagen, laminin, and fibronectin have been shown to promote HNSCC tumor growth, progression, and metastasis [103][104]. Besides, increased expression of fibronectin, tenascin, and decreased expression of laminin, collagen type IV and vitronectin have also been reported to be associated with aggressive HNSCC phenotypes [30][105][106][107]. While the interaction of integrins, particularly α5β1 integrin with fibronectin, and αvβ5 with vitronectin were shown to modulate HNSCC cell behavior, αvβ3-osteopontin, αvβ3-fibronectin, and α5β1-fibronectin interactions are involved in angiogenesis [108]. Overall, ECM plays a very pivotal role in the development and metastasis of tumors by altering the phenotype of stromal or tumor cells, availability of secreted cytokines/chemokines and growth factors, providing acidic and hypoxic conditions for the tumor cells to survive and prevent neoplastic cells from immune attack [109].

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