Abstract
Oral squamous cell carcinoma (OSCC) includes tumors of the lips, tongue, gingivobuccal complex, and floor of the mouth. Prognosis for OSCC is highly heterogeneous, with overall 5-year survival of ~50%, but median survival of just 8–10 months for patients with locoregional recurrence or metastatic disease. A key feature of OSCC is microenvironmental oxygen depletion due to rapid growth of constituent tumor cells, which triggers hypoxia-associated signaling events and metabolic adaptations that influence subsequent tumor progression. Better understanding of leukocyte responses to tissue hypoxia and onco-metabolite expression under low-oxygen conditions will therefore be essential to develop more effective methods of diagnosing and treating patients with OSCC. This review assesses recent literature on metabolic reprogramming, redox homeostasis, and associated signaling pathways that mediate crosstalk of OSCC with immune cells in the hypoxic tumor microenvironment. The likely functional consequences of this metabolic interface between oxygen-starved OSCC and infiltrating leukocytes are also discussed. The hypoxic microenvironment of OSCC modifies redox signaling and alters the metabolic profile of tumor-infiltrating immune cells. Improved understanding of heterotypic interactions between host leukocytes, tumor cells, and hypoxia-induced onco-metabolites will inform the development of novel theranostic strategies for OSCC.
Highlights
Squamous cell carcinoma (SCC) accounts for more than 95% of all cancers affecting the head and neck region, with high rates of associated mortality and morbidity that represent a major public health burden worldwide [1, 2]
In order to better understand the effects of hypoxia on oral squamous cell carcinoma (OSCC), we will require new immunological paradigms that consider how dysregulation of crucial metabolic pathways can impact on both tumor growth and host leukocyte responses
Hypoxia-related metabolic stress inhibits the activity of host immune cells to support oncogenic transformation and inflammation in OSCC
Summary
Squamous cell carcinoma (SCC) accounts for more than 95% of all cancers affecting the head and neck region, with high rates of associated mortality and morbidity that represent a major public health burden worldwide [1, 2]. Hypoxic Immune Metabolism of Oral Cancers functions of infiltrating leukocytes to modify/diminish host defense mechanisms in favor of tumor cell survival [9, 10]. Local oxygen depletion leads to the induction of reactive oxygen species (ROS) that promote cancer cell proliferation and drive autophagic/lysosomal loss of stromal caveolin-1 [an inhibitor of transforming growth factor-β (TGFβ) signaling] in cancer-associated fibroblasts (CAFs), resulting in tumor recurrence and metastasis and affecting patient survival [11,12,13,14]. In order to better understand the effects of hypoxia on OSCC, we will require new immunological paradigms that consider how dysregulation of crucial metabolic pathways can impact on both tumor growth and host leukocyte responses
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