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Neumann et al. J Cancer Metastasis Treat 2018;4:13 I http://dx.doi.org/10.20517/2394-4722.2017.60 Page 3 of 7

Figure 1. Expression of A2BR on cells in the tumor microenvironment. The tumor microenvironment is very heterogeneous. Besides cancer
cells, cancer-associated fibroblasts (CAFs), many different immune cells can infiltrate a tumor, such as tumor infiltrating lymphocytes (TILs),
tumor associated macrophages (TAMs), granulocytic and monocytic myeloid-derived suppressor cells (g and mMDSCs) and dentritic cells
(DCs). While current studies suggest that in TNBC numbers of TILs positively correlate with good patient outcome, TAMs and MDSC do not
T cells predominantly express A2AR and A2BR, in addtion to A1 and A3 receptors. The cAMP-elevating
signaling through A2AR or A2BR in T cells results in inhibition of T-cell receptor-triggered activation of T
cells and of many effector functions, including proliferation, expansion and secretion by T cells of important
[23]
-/-
anti-tumor cytokines such as IFN-g and TNF-a . Studies in Adora2b mice revealed that lack of A2BR
critically diminished regulatory T-cell (Treg) populations, underscoring the important role of A2BR in T-cell
[24]
differentiation . A2AR as well as A2BR are also expressed on macrophages. Similarly, as found in DCs or
T-cells, only A2BR plays a predominant role in the adenosine-dependent differentiation of macrophages.
Once activated, macrophages express T-cell suppressing arginase, indoleamine-2,3-dioxygenase and TGF-b
[25]
and display reduced T cell stimulation which promotes tumor progression . The adenosine binding to
[26]
A2BR results in expansion of the MDSCs pool in tumors and accelerated tumor growth in mice . MDSCs-
expressing A2BR have been successfully targeted with anti-A2BR therapy, suggesting that TNBC patients
may benefit from such therapy as well, because they promote TNBC progression [15,16] . In mouse models
pharmacological blockade of A2BR reduces tumor burden by activating DCs and improving CXCR3-
dependent T cell tumor infiltration in bladder and breast cancer [27,28] . Extensive work in mouse melanoma
models has demonstrated that pharmacological A2BR blockade in combination with dacarbazine reduced
+
tumor growth and significantly increased the number of CD8 T-cells decreases the number of cancer
associated fibroblasts this way contributing to decreased melanoma tumor burden [26,29] . In summary, A2BR is
an abundant protein in the tumor microenviroment.

ADENOSINE RECEPTOR 2B FUNCTIONING IN TNBC
In breast cancer A2AR and A2BR expression varies significantly among breast cancer subtypes. For
example, while A2AR expression levels seem similarly expressed among Pam50 subtypes within the
METABRIC data set (Molecular Taxonomy of Breast Cancer International Consortium), A2BR expression
is significantly higher in basal cancers compared to the other subtypes, such as Her2, LumA and LumB
[30]
[Figure 2] . Expression patterns were confirmed in TCGA (The Cancer Genome Atlas) as well (data not
shown; http://cancergenome.nih.gov). Comparing survival among breast cancer patients defined by the
Pam50 gene expression, showed that basal-like breast cancers with higher A2BR expression showed shorter