Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies

Abstract

The environmental and metabolic pressures in the tumor microenvironment (TME) play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition and activation. Hypoxia triggers a cascade of events that promote tumor growth, enhance resistance to the anti-tumor immune response and instigate tumor angiogenesis. During growth, the developing angiogenesis is pathological and gives rise to a haphazardly shaped and leaky tumor vasculature with abnormal properties. Accordingly, aberrantly vascularized TME induces immunosuppression and maintains a continuous hypoxic state. Normalizing the tumor vasculature to restore its vascular integrity, should hence enhance tumor perfusion, relieving hypoxia, and reshaping anti-tumor immunity. Emerging vascular normalization strategies have a great potential in achieving a stable normalization, resulting in mature and functional blood vessels that alleviate tumor hypoxia. Biomarkers enabling the detection and monitoring of tumor hypoxia could be highly advantageous in aiding the translation of novel normalization strategies to clinical application, alone, or in combination with other treatment modalities, such as immunotherapy.

Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

“…Further, Saggar et al found that chemotherapy repopulates hypoxic cells that contribute to treatment failure, possibly due to enhanced nutrient availability following clearance of rapidly proliferating cells [90]. The link between normoxia and chemotherapeutic success likely explains the benefits of hyperbaric oxygen therapy (HBOT) in improving their effectiveness [91][92][93]. The excess oxygen molecules provided by HBOT enhances chemotherapy-induced oxidative stress, thereby lowering the therapeutic dose and mitigating side effects [91][92][93].…”

“…The link between normoxia and chemotherapeutic success likely explains the benefits of hyperbaric oxygen therapy (HBOT) in improving their effectiveness [91][92][93]. The excess oxygen molecules provided by HBOT enhances chemotherapy-induced oxidative stress, thereby lowering the therapeutic dose and mitigating side effects [91][92][93].…”

“…Immunotherapy has become the fourth pillar of cancer therapy, joining surgery, radiation, and chemotherapy. Hypoxia has been identified as a barrier to the success of immunotherapy due to its association with tumor escape from immune detection [93]. Through stabilization of HIF-1, hypoxia upregulates chemokines such as CCL28, which enhances tumor influx and function of myeloid-derived suppressor cells [94].…”

Tumor hypoxia: an important regulator of tumor progression or a potential modulator of tumor immunogenicity?

“…Studies in cancer patient cohorts have similarly correlated the presence of hypoxia with an immunosuppressed TME in breast cancer, 45 , 46 clear cell renal cell carcinoma, 47 colorectal cancer, 48 hepatocellular carcinoma, 49–51 melanoma, 52 osteosarcoma, 53 neuroblastoma 43 and pancreatic cancer, 41 , 54 among others. 55 These studies used hypoxia gene signatures to determine the hypoxic state and immune fraction or gene set enrichment analysis to highlight the immune microenvironment. In addition, the coupling of an immune score with a hypoxia score in lung adenocarcinoma, 42 pancreatic cancer, 41 and soft tissue sarcoma 38 revealed significantly lower immune activation in tumors with high hypoxia, compared to their low hypoxia counterparts.…”

New Insights Into the Regulatory Roles of Extracellular Vesicles in Tumor Angiogenesis and Their Clinical Implications

“…Many proangiogenic factors are upregulated in tumor cells and tumor-associated stromal cells, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and delta ligand-like 4 (Dll4). Hypoxia is a key inducer of tumor angiogenesis and promotes the expression of various proangiogenic factors in the tumor microenvironment ( Abou Khouzam et al, 2020 ). Recently, antiangiogenic drugs have been widely applied to the treatment of multiple solid cancers, and cancer patients have gained tremendous survival benefits from antiangiogenic therapy.…”