“Suffocating” tumors by blocking adaptation to hypoxia: a new headway in melanoma immunotherapy

Figures & data

Figure 1. Targeting the transcription activity of Hif1a recruits immune cells to the melanoma tumor microenvironment. a: Melanoma tumors are characterized by the presence of poorly oxygenated areas [Oxygen pressure (pO₂) less than 8 mmHg]. These hypoxic areas result from an imbalance between low O₂ supply due to an abnormal vascularization and high O₂ consumption by tumor cells. Hypoxic areas are poorly infiltrated by cytotoxic immune cells. b: Under a low pO₂ or hypoxic microenvironment, the enzymatic activity of prolyl hydroxylase domain-2 (Egln1/Phd2) protein is inhibited. Such inhibition leads to blocking the prolyl hydroxylation (OH) of Hif1a, inhibition of both Hif1a-dependent ubiquitination (Ub) and Von Hippel-Lindau (Vhl) interaction, and subsequent proteasomal degradation of Hif1a (B1). Consequently, Hif1a accumulates in the cytoplasm, translocates to the nucleus, and forms a heterodimer with hypoxia-inducible Factor-1β (Arnt). The Hif1a/Arnt complex binds to the hypoxia-responsive element (HRE) and activates transcription of several downstream target genes (B2). c: Inhibiting the transcription activity of Hif1a can be achieved by deleting the domain responsible for the formation of a heterodimer with Arnt using CRISPR/Cas9 gene-editing technology (C1). In hypoxic cells expressing deleted Del-Hif1a, the formation of heterodimer Hif1a/Arnt is prevented, and the transcription activity of Hif1a is blocked. In these cells, the expression of the pro-inflammatory (C-C motif) ligand 5 chemokine (Ccl5) is activated by a mechanism that is not fully understood. The release of Ccl5 by tumor cells expressing Del-Hif1a increases the recruitment of cytotoxic immune cells in the microenvironment, which subsequently release of (C-C motif) ligand 2 chemokine (Ccl2) to support the establishment of inflammatory signature in melanoma (C2)