Abstract
Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized conditions that act to dampen immune cell function. Through its impact on key cancer hallmarks and by creating a physical barrier conducive to tumor survival, hypoxia modulates tumor cell escape from the mounted immune response. The tumor cell-immune cell crosstalk in the context of a hypoxic TME tips the balance towards a cold and immunosuppressed microenvironment that is resistant to immune checkpoint inhibitors (ICI). Nonetheless, evidence is emerging that could make hypoxia an asset for improving response to ICI. Tackling the tumor immune contexture has taken on an in silico, digitalized approach with an increasing number of studies applying bioinformatics to deconvolute the cellular and non-cellular elements of the TME. Such approaches have additionally been combined with signature-based proxies of hypoxia to further dissect the turbulent hypoxia-immune relationship. In this review we will be highlighting the mechanisms by which hypoxia impacts immune cell functions and how that could translate to predicting response to immunotherapy in an era of machine learning and computational biology.
Highlights
Solid tumors manifest in a microenvironment that harbors an array of cellular and non-cellular factors, cycling through various environmental pressures, which contribute to shaping a tumor’s immunological features [1]
Clinical benefit from cancer immunotherapy has been limited to a minority of patients
Achieving benefit in the majority of patients necessitates a wholistic understanding of anti-tumor response mechanisms and both the cell-intrinsic and extrinsic molecules involved in primary, adaptive, as well as acquired resistance to immunotherapy
Summary
Solid tumors manifest in a microenvironment that harbors an array of cellular and non-cellular factors, cycling through various environmental pressures, which contribute to shaping a tumor’s immunological features [1]. Hypoxic tumor microenvironment is associated with immune evasion through expression of immune checkpoints (programmed death ligand -1), downregulation of type-I interferon signaling, shedding of antigen presenting molecules (MHC class I), enrichment of immunosuppressive cytokines and aggregation of immune suppressive cells (MDSC and Tregs) in the TME [187]. In this regard, recent attempts to target hypoxic cells selectively with hypoxia activated prodrugs have yielded encouraging results with a significant antitumor response to immune checkpoint blockade. Despite the simplicity and ease of use of current computational tools, they should not be used as a standalone analysis platform to conclude on the immune activation state of a tumor
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