Immunoregulatory activity of adenosine and its role in human cancer progression

Abstract

The adenosinergic pathway plays an important role in cancer progression. Aside from regulating functions of tumor cells and tissue cells present in the tumor microenvironment, extracellular adenosine is an autocrine or paracrine factor with powerful immunoregulatory activity. Adenosine signaling downregulates functions of most immune effector cells but enhances expansion and activity of immune cells responsible for suppression of anti-tumor immune responses. Adenosine is critical for limiting potential tissue-destructive effects of activated immune cells. It also facilitates tumor escape from the immune control. This review illustrates the involvement of adenosine and its four receptors, A₁R, A_2AR, A_2BR and A₃R, in the complex regulation of cellular and molecular cross talk that contributes to cancer progression. It also considers the potential of therapeutics targeting the adenosinergic pathway for benefiting cancer patients.

Keywords::

• 5′-adenosine monophosphate
• adenosine
• adenosine deaminase
• adenosine receptors
• ATP
• cancer
• CD39 and CD73 expression
• immune cells
• inflammation
• tumor immune escape
• tumor microenvironment

Financial & competing interests disclosure

The authors were supported in part by NIH grant RO-1CA168628 (TL Whiteside) and by the Swiss National Foundation grant #PBSKP3-1401119/7 (L Muller). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Adenosine (ADO) has been shown to play a central role in regulating functions of immune cells in inflammatory environments.

• Under normal physiologic conditions, ADO downregulates functions of activated immune cells, thus preventing tissue destruction and serving as a ‘danger signal’.

• In the tumor microenvironment (TME), ADO levels are increased relative to those in normal interstitial tissues in response to hypoxia, ischemia, necrosis or inflammation associated with the tumor growth.

• In the TME, the ADO pathway is subverted to promote tumor progression by inhibiting functions of immune anti-tumor effector cells via the A_2AR or A_2BR or by activating/expanding suppressor cells (e.g., Treg or myeloid-derived suppressor cells).

• The presence, subtype and expression levels of the ADO receptors in immune cells determine whether ADO delivers inhibitory or stimulatory signals.

• ADO contributes to tumor metastasis by directly altering functional characteristics of tumor cells, and also by protecting these cells from anti-tumor activities mediated by immune effector cells.

• Pharmacologic modulation of ADO receptors or components of the ADO pathway appears to be effective in inhibiting tumor growth in vitro and in vivo in mouse tumor models.

• Translation of pre-clinical studies with ADO pathway-reactive pharmacologic agents into human clinical trials will require further insights into mechanisms ADO utilizes to alter functions of different cells in the TME.

Notes