Tumor microenvironment: an evil nexus promoting aggressive head and neck squamous cell carcinoma and avenue for targeted therapy

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a poor prognosis for advanced-stage tumors. Recent clinical, genomic, and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC. Despite significant advances in multimodal therapeutic interventions, failure to cure and recurrence are common and account for most deaths. It is becoming increasingly apparent that tumor microenvironment (TME) plays a critical role in HNSCC tumorigenesis, promotes the evolution of aggressive tumors and resistance to therapy, and thereby adversely affects the prognosis. A complete understanding of the TME factors, together with the highly complex tumor-stromal interactions, can lead to new therapeutic interventions in HNSCC. Interestingly, different molecular and immune landscapes between HPV^+ve and HPV^-ve (human papillomavirus) HNSCC tumors offer new opportunities for developing individualized, targeted chemoimmunotherapy (CIT) regimen. This review highlights the current understanding of the complexity between HPV^+ve and HPV^-ve HNSCC TME and various tumor-stromal cross-talk modulating processes, including epithelial-mesenchymal transition (EMT), anoikis resistance, angiogenesis, immune surveillance, metastatic niche, therapeutic resistance, and development of an aggressive tumor phenotype. Furthermore, we summarize the recent developments and the rationale behind CIT strategies and their clinical applications in HPV^+ve and HPV^-ve HNSCC.

Fig. 1

Head and neck squamous cell carcinoma (HNSCC) TME is a complex ecosystem. HNSCC TME is a complex ecosystem consisting of a fabricated network of tumor cells surrounded by non-tumor cells, including cancer-associated fibroblasts (CAFs), endothelial cells (EC), adipocytes, neuroendocrine cells, blood and lymphatic vascular cells, muscle cells, infiltrating immune cells ((T cells, B cells, natural killer cells (NK cells), neutrophils, dendritic cells (DC), Langerhans cells (LCs), macrophages, and myeloid-derived suppressor cells (MDSCs)]. In addition, stromal components, including extracellular matrix (ECM) proteins (collagen, fibronectin, elastin, laminin, and tenascin), intermediate metabolites, nutrients, hormones, growth factors, etc. are the crucial components of HNSCC TME. The complex cross talk between the tumor and the stromal components regulates cell growth, epithelial–mesenchymal transition (EMT), invasion and metastasis, anoikis resistance, angiogenesis, metastatic niche, immune surveillance, and therapeutic resistance making HNSCC tumors very aggressive

Fig. 2

TME of HPV^+ve and HPV^−ve HNSCC tumors. The HPV^+ve (left) and HPV^−ve (right) HNSCC TME have different cell composition and differential tumor–stromal cross talk. The HPV^+ve tumors show increased infiltration of CD3⁺, CD4⁺, CD8⁺ cells, CD56^dim NK cells, APCs, MDSCs, DCs, and lower Tregs infiltration; however, the converse is true for HPV^−ve tumors. HPV^−ve tumors have increased the infiltration of M1 macrophages and Langerhans cells. As compared to HPV^−ve tumors, HPV^+ve tumors have increased secretion of various cytokines, chemokines, and growth factors, including IL-10, CCL2, IL-6, TGF-β, TNF-α, and EGF that provide a growth advantage to the tumor cells and induce immunosuppression. Increased secretion of TGF-β and CCL2 by the HPV^+ve cells promotes macrophage differentiation to pro-tumorigenic M2 that stimulates Tregs. In turn, Tregs induce LT CD8⁺ exhaustion and apoptosis through PD-L1-PD-1 interaction. M2 secretes IL-6 and IL-10 that stimulate MDSCs, TGF-β and EGF induces epithelial-to-mesenchymal transition (EMT) on cancer cells. While the HPV^+ve tumors have enhanced OXPHOS at the core and aerobic glycolysis in the tumor periphery (blue zone), the opposite is true for HPV^−ve tumors and has more deposition of lactate known to suppress the immune cells

Fig. 3

Formation of Emboli and anoikis resistance. After tumor cells leave the primary tumors and invade into the blood circulation, they activate the platelets that encase them to protect them from the shear stress and immune attack. Platelets through the secretion of VEGF, PDGF, or TGF-β promote downregulation of NKG2D receptor and induce NK cells anergy. By arresting tumor cells at the vascular wall via P-selectin and its ligands, platelets facilitate extravasation and distant metastasis

Fig. 4

Schematic showing the immunotherapeutic approaches targeting the HNSCC TME. Inactivation of CTLs by secretory immunomodulators or immune checkpoints promotes immune escape of cancer cells. While B7 ligands on APCs interact with CD28 on CTL and provide a secondary signal for their activation and immune response, CTLA-4 on Tregs interfere in this interaction, suppresses CTLs activity and enhances Treg activity. In addition, increased PD-L1 on cancer cells or immune cells like NK, MDSCs, M2 macrophages, and Tregs bind to its receptor PD-1 on activated T cells to promote the state of anergy in CTLs. The OX40 ligand on the APC cells interacts with the OX40 receptor on T cells and increase CTL activation. Cancer cells secrete VEGF, which, upon binding with its receptor VEGFR on endothelial cells, promotes angiogenesis. Many pharmacological inhibitors, including monoclonal antibodies/agonists of immune checkpoints, are being tested in HNSCC and shown to restore CTL antitumor activity and relieve immunosuppression