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.

Adaptive Mechanisms of Tumor Therapy Resistance Driven by Tumor Microenvironment

“…The adaptive resistance to cancer treatment driven by the TME may play a vital role in tumor recurrence and metastasis. Therefore, a variety of approaches targeting the TME have been developed to reverse resistance to radiotherapy, chemotherapy, and immunotherapy (Xu et al, 2015;Zhang et al, 2015;Hu et al, 2017;Tan et al, 2018;Bhat et al, 2021). Hijacking the TME to increase drug delivery has also been demonstrated to enhance the efficacy of chemotherapeutic drugs (Fang et al, 2018;Amini et al, 2019).…”

The Use of Iron Oxide Nanoparticles to Reprogram Macrophage Responses and the Immunological Tumor Microenvironment

“…Cancer is a complex and heterogeneous disease that involves the dysregulation of various cell processes, such as metabolism ( 19 ), proliferation ( 20 ), intracellular pH dynamics ( 21 ), redox signaling ( 22 ), and migration/invasion ( 23 , 24 ). The complexity of this disease is also reflected by the different ecosystems that constitute a permissive TME ( 25 , 26 ). A close inspection of the TME reveals a network of cellular and non-cellular components that provide the signals that control tumor cell survival, proliferation, angiogenesis, immune evasion and metastasis.…”

Chemokine-Cytokine Networks in the Head and Neck 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 [ 23 ]. 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) [ 24 ]. 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 [ 25 ], host immunosuppression [ 14 ], and promote the development of aggressive tumors [ 22 ] ( Figure 1 ).…”