Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Abstract

The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.

Keywords: autophagy and antitumor immune response; cancer stem cells; circulating tumor cells; epithelial-mesenchymal transition; hypoxia; hypoxia-inducible factor; immune suppression; lymphoid cells; myeloid cells; programmed death-ligand 1; tumor microenvironment.

Fig. 1.

Hypoxic stress impairs tumor cell susceptibility to cytotoxic T lymphocyte (CTL)-mediated lysis through induction of hypoxia-inducible factor (HIF)-1α, phosphorylated STAT3 (pSTAT3), and autophagy. Under hypoxia, tumor cells stabilize HIF-1α and activate pSTAT3, which renders them resistant to CTL-mediated lysis. Similarly, hypoxia-induced autophagy is responsible for the acquisition of resistance to CTL-mediated killing by selective degradation of pSTAT3 under autophagy inhibitions under hypoxia (78, 82).

Fig. 2.

Hypoxia-induced autophagy in cancer cells acts as an intrinsic resistance mechanism to natural killer (NK) cell-mediated killing. After recognition by NK cells, the cytolytic effectors perforin 1 and granzyme B enter the target cells through endocytosis and traffic to enlarged endosomes, called “gigantosomes.” In normoxic cells, perforin forms pores in the gigantosome membrane, allowing granzyme B release and initiation of cell death. In hypoxic cells, excessive autophagy leads to fusion of gigantosomes with autophagosomes and the subsequent formation of amphisomes, which contain granzyme B and perforin 1. Fusion of amphisomes with lysosomes triggers selective degradation of granzyme B, making hypoxic tumor cells less sensitive to NK cell-mediated killing (114).

Fig. 3.

Influence of hypoxia on tumor microenvironment-mediated immune cell recruitment. Under hypoxia, the tumor microenvironment recruits tolerance-inducing immune cells: T regulatory cells and M2 tumor-associated macrophages. When normalized, tumor vessels alleviate hypoxia and change the cell recruitment signals (cytokines) to attract immunocompetent programmed death-ligand 1 (PD-L1)-positive cells, such as NK cells and CTLs. Hypoxia compensation reduces expression of immune checkpoint ligands (PD-L1 and PD-L2) on tumor cells, immune suppressor cells, and endothelial cells, allowing the immune cells to extravasate the normalized vessel wall, meet tumor cells, and exert their cytotoxic action.