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Adenosine A2B receptor blockade slows growth of bladder and breast tumors

Caglar Cekic1, Duygu Sag, Yuesheng Li

  • 1Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|November 26, 2011
PubMed

Insights

Blocking adenosine A(2B) receptors (A(2B)ARs) with aminophylline or ATL801 inhibits tumor growth and metastasis. This effect is mediated by enhanced dendritic cell activation and T-cell responses via the CXCR3 pathway.

Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • High adenosine levels in tumors suppress immune responses by activating A(2A) and A(2B) receptors on immune cells.
  • Previous studies suggested A(2A) receptor blockade activates antitumor T cells and dendritic cells (DCs).

Purpose of the Study:

  • To evaluate the effects of aminophylline (a nonselective adenosine receptor antagonist) and ATL801 (a selective A(2B)AR antagonist) on tumor growth and metastasis.
  • To elucidate the specific adenosine receptor subtype involved in the observed antitumor effects.

Main Methods:

  • Intermittent intratumor injection of aminophylline and ATL801 in syngeneic mouse models (MB49 bladder, 4T1 breast cancer).
  • Assessment of tumor growth, metastasis, immune cell infiltration (T cells, DCs), and cytokine/chemokine levels (IFN-γ, CXCL10).
  • Experiments utilizing knockout mice (A(2A)AR-/-, A(2B)AR-/-, CXCR3-/-, RAG1-/-) and bone marrow chimeras.

Main Results:

  • Both aminophylline and ATL801 significantly slowed tumor growth and reduced lung metastasis by 85%.
  • The antitumor effects were unexpectedly attributed to A(2B)AR blockade, not A(2A)AR blockade.
  • Treatment increased tumor levels of IFN-γ and CXCL10, correlating with increased activated CXCR3(+) T cells and reduced endothelial cell precursors.
  • Inhibition of tumor growth was abolished in CXCR3-/- and RAG1-/- mice, indicating a T-cell-dependent mechanism.
  • A(2B)AR deletion enhanced CD86 expression on DCs in RAG1-/- mice.

Conclusions:

  • Blockade of A(2B)ARs, rather than A(2A)ARs, is responsible for the antitumor effects of aminophylline.
  • A(2B)AR antagonism enhances DC activation and promotes CXCR3-dependent antitumor immune responses.
  • Targeting A(2B)ARs represents a promising strategy for cancer immunotherapy.

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