Hypoxia-/HIF-1α-Driven Factors of the Tumor Microenvironment Impeding Antitumor Immune Responses and Promoting Malignant Progression

Abstract

The metabolic tumor microenvironment (TME) is characterized inter alia by critical oxygen depletion (hypoxia/anoxia), extracellular acidosis (pH ≤ 6.8), high lactate levels (up to 40 mM in heterogeneously distributed areas), strongly elevated adenosine concentrations (10-100 μM) and declining nutrient resources. These TME features are major drivers, e.g., for genetic instability, intratumor heterogeneity, malignant progression and development of resistance to conventional anticancer therapies. In this context, hypoxia-dependent (and non-hypoxic) HIF-1α activation plays a key role in orchestrating a multifaceted (local) suppression of innate and adaptive antitumor immune responses (and of immune-based tumor treatment). Besides the characteristic traits mentioned, the immune-suppressive actions can additionally be triggered by an (over-)expression of VEGF and activation of VEGFR, and externalisation of phosphatidylserine from the inner to the outer membrane leaflet of cells and exosomes. Altogether, and even individually, these features provide strong immune-suppressive signals. The downstream effects of an enhanced HIF-1α expression include (a) an activation of immune-suppressive effects (recruitment and stimulation of immune-suppressor cells [e.g., Treg, MDSC], secretion of immune-suppressive TH2-type cytokines), and (b) inhibition of antitumor immune responses (inhibition of immune cell actions [e.g., NK, NKT, CD4, CD8], inhibition of antigen-presenting cells [e.g., DC], reduced production of immune-stimulatory TH1-type cytokines).

Role and mechanism of programmed death‑ligand�1 in hypoxia‑induced liver cancer immune escape (Review)

“…Previous studies have revealed that tumor hypoxia alters the composition and activity of tumor-associated immune cells, and that numerous immune cells with immunosuppressive activities are recruited to tumor tissues to form the immunosuppressive microenvironment (18,50,51). Under hypoxic conditions, tumor cells and macrophages secrete a variety of cytokines and chemokines, including C-C motif chemokine (CCL)22, CCL28 and IL-10, which results in the recruitment of CD4 + CD25 + FOXP3 + Tregs from peripheral blood to inhibit T cell-mediated antitumor responses (18,52,53). Hypoxia also promotes the recruitment of MDSCs (19).…”

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…Cancer cells often suffer from hypoxia, nutrient (glucose and amino acid), and energy deprivation resulting from insufficient vasculature and blood supply [1]. These stress conditions are key factors imposed on proliferating tumor cells to trigger their malignant transformation and to enable them to overcome or escape antitumor immune surveillance and to avoid cellular senescence and apoptosis [2][3][4]. This results in tumor progression and aggressiveness, genetic instability, development of chemo-and radio-resistance, and poor prognosis [5,6].…”

Connections between Metabolism and Epigenetic Modification in MDSCs

“…In the TME, MDSCs have extensive glycolysis due to the presence of hypoxia conditions. The glycolytic pathway of MDSCs is regulated by hypoxia inducible factor-1α (HIF-1α), which enhances the immunosuppressive function of MDSCs [ 25 , 26 , 27 , 28 ]. HIF-1α was found to be the main cause of the tumor microenvironment effect on the differentiation and function of MDSCs ( Figure 1 ) [ 25 ].…”