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

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 mu M) 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 nonhypoxic) HIF-1 alpha 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-1a 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).