Hypoxia as a Modulator of Inflammation and Immune Response in Cancer

Abstract

A clear association between hypoxia and cancer has heretofore been established; however, it has not been completely developed. In this sense, the understanding of the tumoral microenvironment is critical to dissect the complexity of cancer, including the reduction in oxygen distribution inside the tumoral mass, defined as tumoral hypoxia. Moreover, hypoxia not only influences the tumoral cells but also the surrounding cells, including those related to the inflammatory processes. In this review, we analyze the participation of HIF, NF-κB, and STAT signaling pathways as the main components that interconnect hypoxia and immune response and how they modulate tumoral growth. In addition, we closely examine the participation of the immune cells and how they are affected by hypoxia, the effects of the progression of cancer, and some innovative applications that take advantage of this knowledge, to suggest potential therapies. Therefore, we contribute to the understanding of the complexity of cancer to propose innovative therapeutic strategies in the future.

Keywords: HIF-1α; NF-κB; STAT; cancer; hypoxia; inflammation; tumoral microenvironment.

Figure 1

HIF-1α pathway. In normoxia (left), HIF-1α is hydroxylated by PHDs to be recognized by VHL, which adds ubiquitin units to send HIF-1α to the proteosome to be degraded. In hypoxia (right), PHDs are inactivated and HIF-1α is translocated to the nucleus, forming a dimmer with HIF-1β to induce the transcription of several target genes. VEGF, Vascular Endothelial Growth Factor; EPO, erythropoietin; LDH, Lactate Dehydrogenase; TGF-β, Transforming Growth Factor β; CAIX, Carbonic Anhydrase 9; MMP2, Matrix Metallopeptidase 2; GLUT1, Glucose transporter 1.

Figure 2

Interrelation between the HIF pathway, inflammation, and cancer. (a) In ccRCC, VHL is inactive, leading to HIF-1α and HIF-2α accumulation. As a consequence, there is a decrease in antitumoral response due to low levels of HIF-1α, IFN, and CD8+ inactivated cells. (b) Inflammation- induced by COPD with the overexpression of HIF-1α leads to overactivation of KRAS signaling and cancer. (c) Viruses such as HBV also induce inflammation that synergizes with hypoxia as factors to induce cancer. (d) Correlation between the expression of TLR and nuclear HIF-1α was observed in early carcinogenesis of the pancreas. (e) IL-6, NF-κB, and IFN-α induce the overexpression of HIF-1α; indirectly, TNF-α and MCP1 also induce HIF-1α through the NF-κB/COX2 axis. HIF-1α also induces the expression of COX2. (f) HIF-1α stimulates TAMs and tumoral cells to release IL-1β, which stimulates CAFs. Tumoral cells also secrete TGF-β. (g) HIF-1α induces and regulates the expression of CD39 and CD73 to obtain eADO. (h) Hypoxic tumoral cells release exosomes enriched with molecules, such as TGFβ-inducing M2 TAMs recruitment. Abbreviations: clear cell renal cell carcinoma, ccRCC; chronic obstructive pulmonary disease, COPD; hepatitis B virus, HBV; toll-like receptors, TLR; interleukin 1-beta, IL-1β; tumor necrosis factor-α, TNF-α; interferons, IFN; monocyte chemoattractant protein 1, MCP1; extracellular adenosine, eADO. See more details in the main text. Lung icon of Figure 2b is from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/, accessed on 2 January 2022).

Figure 3

Canonical and non-canonical pathway of NF-κB. On the (left), p50/p65 subunits are inhibited by IκBs; however, when the pathway is activated, IκBs are phosphorylated by the IKK complex integrated by IKKα, IKKβ, and IKKγ and sent to degradation. Then, the p50/p65 are released and translocated in the nucleus to activate the transcription of the target genes. On the (right), in the non-canonical pathway, RelB is sequestered by p100. When the pathway is activated, IKKα phosphorylates and sends p100 to degradation. Then, RelB is released and forms a dimer with p52, which is translocated to the nucleus. Abbreviations: IκB kinase complex (IKK); Transforming growth factor-β–activated kinase 1 (TAK); NF-κB-Inducing Kinase (NIK).

Figure 4

STAT pathway. After the interaction of the ligands with their corresponding receptors, associated tyrosine kinases, such as JAKs, are transphosphorylated to then phosphorylate the cytoplasmic tail receptors. Then, STATs are recruited, and both are phosphorylated to form dimers that are translocated into the nucleus to activate gene transcription (see details in the text).

Figure 5

Intercommunication between HIF, NF-κB, and STAT pathways during hypoxia. Hypoxia induces NF-κB activity through CaMK2 and the presence of TAK and IKK, leading to the sumoylation of IκBα. TNF-α also increases HIF-1α levels through the NF-κB pathway. Hypoxia through HIF-1α also induces phosphorylation of the inhibitory IκBα for its degradation and thus activation of NF-κB. Moreover, hypoxia inactivates the PHD hydroxylation over IKKβ, which conducts IKKβ to degradation; instead, IKKβ phosphorylates IκBα to finally activate NF-κB. STAT3 induces HIF-1α expression and avoids its degradation, even independently of hypoxia, inducing gene transcription. STAT3 and HIF-1α interact and recruit coactivators to induce gene transcription, including VEGF. Hypoxia induces the expression of Src, which leads to STAT3 activation and, in consequence, HIF-1α stabilization. Akt is also activated by STAT3, and as feedback, induces HIF-1α expression. miR17 and miR20a inhibit differentiation and STAT3 activation. However, HIF-1α inhibits these miRNAs and avoids their effects (see more details in the main text).

Figure 6

Intercommunication between tumoral and immune cells in hypoxia. Hypoxia triggers the activation of HIF-1α, NFκB, and STAT pathways, boosting the transcription and releasing of chemotactic factors (CXCL12, VEGF, and CCL-2, -5, -7, -8, -12 and -26), pro-inflammatory cytokines (TNF-α, TNFβ, and IL-1,-6) as well as the secretion of exosomes, PD-L1, lactate, PGE2, ROS, and NO, among other molecules that targets immune cells. Red arrows represent the stimulation of immune cells, whereas red truncated arrows represent inhibition. These signal molecules activate several mechanisms that result in the infiltration of pro-tumor immune cells, such as TAMs, MDSCs, CAFs, Ns, and Treg cells, to the tumor, which suppress the anti-tumor response of CD8+ cells, B cells, NK cells, and dentric cells (DCs). Immune cells, in response, release IL-1β, -4, -6, -8, -10, -12, -13, -17, CCL-1, -2, -3, -5, -22, TNFα, TNF-β, IFN-γ,M- CSF, VEGF, bFGFβ, PDGF, PDL1, MMP-2,-9, Arg-1, NOX2, and COX-2 as well as the release of glutamate, pyruvate, and lactate among other molecules, resulting in the promotion of inflammation, metabolic adaptations, growth of tumors, epithelial to mesenchymal transition, angiogenesis, migration, invasion, metastasis, and resistance to chemo, radio, and immune therapy. Black arrows represent the stimulation of tumoral cells, whereas black truncated arrows represent inhibition. See main text for more details.