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Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer

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Abstract

The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also underscored the need to better understand the mechanisms that prevent tumor rejection and survival even after the blockade of immunological negative regulators. Here, we describe the implications of the “metabolism-based” immunosuppressive mechanism, where the local tissue hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2 adenosine receptors on the surface of activated immune cells. This molecular pathway is of critical importance in mechanisms of immunosuppression in inflamed and cancerous tissue microenvironments. The protection of tumors by tumor-generated extracellular adenosine and A2 adenosine receptors could be the misguided application of the normal tissue-protecting mechanism that limits excessive collateral damage to vital organs during the anti-pathogen immune response. The overview of the current state of the art regarding the immunosuppressive effects of extracellular adenosine is followed by a historical perspective of studies focused on the elucidation of the physiological negative regulators that protect tissues of vital organs from excessive collateral damage, but, as a trade-off, may also weaken the anti-pathogen effector functions and negate the attempts of anti-tumor immune cells to destroy cancerous cells.

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Acknowledgment

This work was supported in part by The National Institutes of Health (R01 CA112561 and R01 CA111985).

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  1. New England Inflammation and Tissue Protection Institute, Northeastern University, 113 Mugar Health Sciences Building, 360 Huntington Ave., Boston, MA, 02115, USA

    Michail Sitkovsky & Akio Ohta

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  1. Michail Sitkovsky
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Correspondence to Michail Sitkovsky.

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Sitkovsky, M., Ohta, A. Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer. J Mol Med 91, 147–155 (2013). https://doi.org/10.1007/s00109-013-1001-9

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