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Critical Reviews™ in Immunology
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ISSN Druckformat: 1040-8401
ISSN Online: 2162-6472

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Critical Reviews™ in Immunology

DOI: 10.1615/CritRevImmunol.2019030168
pages 505-524

Tumor Hypoxia: A Key Determinant of Microenvironment Hostility and a Major Checkpoint during the Antitumor Response

Amirtharaj Francis
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
Goutham Hassan Venkatesh
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
Rania Faouzi Zaarour
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
Nagwa Ahmed Zeinelabdin
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
Hussam H. Nawafleh
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
Prathibha Prasad
Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
Stéphanie Buart
INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Faculty de Médecine University Paris-Sud, University Paris-Saclay, Villejuif F-94805, France
Stéphane Terry
INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, Faculty de Médecine University Paris-Sud, University Paris-Saclay, Villejuif F-94805, France
Salem Chouaib
UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par La Ligue Contre Le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France; Thumbay Research Institute for Precision Medicine Gulf Medical University, Ajman, UAE; P.O. Box 4184, Ajman, United Arab Emirates

ABSTRAKT

Recent antitumor immunotherapies such as monoclonal antibodies targeting immune checkpoints have led to outstanding results in several cancers. However, despite the favorable outcomes for responding patients, the response rate remains relatively low. This is in part due to the influence of the tumor microenvironment (TME) in protecting the tumor from the antitumor immune response and facilitating immune escape. Tumor hypoxia is one of the most important features of the TME, exerting an adverse effect on tumor aggressiveness and patient prognosis. Hypoxic stress interferes with immune plasticity and promotes tumor heterogeneity and progression. Cellular adaptation to hypoxia is primarily mediated by a family of transcriptional regulators, hypoxia-inducible factor (HIF). Apart from hypoxia, the HIF pathway is modulated in a hypoxia-independent manner. HIF-1α stabilization and activity are regulated by epigenetic changes and mutations. Strong evidence indicates that tumor hypoxia controls malignant and metastatic phenotype of cancer cells and therefore presents a unique therapeutic challenge in the treatment of solid malignancies. An alluring alternative strategy to reinvigorate anticancer immune responses comes from the emerging field of TME and its associated pathways. Targeting hypoxia or its associated pathways may therefore offer new options in the design of innovative cancer immunotherapy approaches. In this article, we briefly review the potential of hypoxic stress on tumor plasticity and stromal reactivity as well as the possible targeting of hypoxia-induced pathways to increase immunotherapy efficiency.


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