Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma

Abstract

Background: Changes in the tumor microenvironment and immune surveillance represent crucial hallmarks of various kinds of cancer, including oral squamous cell carcinoma (OSCC), and a close crosstalk of hypoxia regulating genes, an activation of chemokines and immune cells has been described.

Methods: A review about the pivotal role of HIF-1, its crosstalk to various cornerstones in OSCC tumorigenesis is presented.

Results: Hypoxia is a frequent event in OSCC and leads to a reprogramming of the cellular metabolism in order to prevent cell death. Hypoxic OSCC cells induce different adaptive changes such as anaerobic glycolysis, pH stabilisation and alterations of the gene and protein expression profile. This complex metabolic program is orchestrated by the hypoxia inducible factor (HIF)-1, the master regulator of early tumor progression. Hypoxia-dependent and -independent alterations in immune surveillance lead to different immune evasion strategies, which are partially mediated by alterations of the tumor cells, changes in the frequency, activity and repertoire of immune cell infiltrates and of soluble and environmental factors of the tumor micromilieu with consecutive generation of an immune escape phenotype, progression of disease and poor clinical outcome of OSCC patients.

Conclusions: This review focusses on the importance of HIF-1 in the adaption and reprogramming of the metabolic system to reduced oxygen values as well as on the role of the tumor microenvironment for evasion of OSCC from immune recognition and destruction.

Keywords: Hypoxia; Immune escape; Immune response; Metabolic adaption; Oral squamous cell carcinoma.

Fig. 1

General pathways in oral squamous cell carcinoma as downstream products after hypoxic stabilisation of HIF. GLUT-1 Glucose transport molecule -1, VEGF Vascular endothelial growth factor, NHE Natrium/hydrogen exchanger, MCT Monocarboxylate transporter, CA IX Carbonic anhydrase 9, PDL-1 Programmed cell death ligand, CTL Cytotoxic T lymphocyte

Fig. 2

HIF-triggered complex system for pH stabilization. MCT Monocarboxylate exchanger, CAIX Carbonic anhydrase 9, NHE 1 Sodium/hydrogen exchanger

Fig. 3

Complex system of adaption to hypoxic stress in early carcinogenesis (a) and mechanisms for immune escape (b)

Fig. 4

Differential expression of hypoxia markers and HLA class I in OSCC-carboanhydrase (CA) IX ¹, hypoxia inducing factor (HIF) 1α ², beta2-microglobulin (β2-m) ³ and heavy chain (HC)-10 ⁴ in human head and neck squamous cell carcinoma (OSCC)