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mast cells and other white blood cells. In breast cancer, TILs play an important role in mediating positive
responses to chemotherapy and improving clinical outcomes. Specifically, in patients with HER2-positive
breast cancer and TNBC, large adjuvant studies have shown that higher levels of TILs in primary biopsies
were associated with prolonged overall survival (OS) and fewer recurrences, independent of therapy [4-6] .
Similar results were also obtained in patient cohorts treated with neoadjuvant therapy. Here, increased
[7-9]
levels of TILs in primary biopsies correlated with a higher pathological response rate (pCR) . On the
other hand, tumor-associated macrophages (TAMs) that derive from peripheral blood monocytes are
recruited to the TNBC tumor microenvironment and undergo activation that leads to the secretion of
inhibitory cytokines, the reduction of effector functions of TILs and the promotion of regulatory T cells
[10]
(Treg) . High levels of TAMs are associated with distant metastasis in TNBC in humans and can be
blocked by targeting the chemokine ligand 5 (CCL5) in a mouse model [11,12] . A growing body of evidence
suggests that tumor-infiltrated immune cells from myeloid origin (myeloid-derived suppressor cells,
MDSCs) differentiate into cells that promote tumor progression and metastasis in addition to their
immunosuppressive role [13,14] . In a TNBC mouse model it was demonstrated that while monocytic
(m)MDSCs infiltrated primarily the primary tumor, granulocytic (g)MDSCs homed to metastases in the
[15]
lung . In humans, gMDSCs were found to increase with neoadjuvant breast cancer therapies in patients
[16]
showing no pathologic responses . Collectively, this suggests that a group of TNBC can benefit from
targeted immunotherapies. How can this TNBC patient cohort be identified?

TNBC is a heterogeneous breast cancer. Based on 3247 gene expression profiles, 21 breast cancer data
sets have been analyzed that resulted in subtyping of TNBC which has been proven useful to decipher
responses of TNBC patients to neoadjuvant therapies [17,18] . For example, patients in the basal-like 1 (BL
1) subgroup showed the highest pathological complete response of 41% compared to the basal-like 2
(BL 2) and the luminal androgen receptor (LAR) subgroup, 18% and 29%, respectively [17,18] . In addition,
classifying then a TNBC cohort (587 patients) in three groups based on the amount of immune cell
infiltration in the tumor, allowed to examine an immune signature comprising B- and T-cell markers that
include immune-suppressive as well as immune-activating genes in these TNBC subtypes. This analysis
revealed that out of all 587 TNBC cases, the ones correlating highest with the immune signature, were found
mostly in the BL1 subtype. Interestingly, the M subgroup showed a strong negative correlation (Spearman,
[17]
-0.95) . As the BL1 subtype is characterized by elevated cell cycle and DNA response genes, it may that
the higher mutation rate of this TNBC subtype causes aberrant proteins expression that in turn attracts
immune infiltrates. In aggregate, this suggests that TNBC patients subtyping by gene expression studies in
conjunction with histopathological tissue analyses should be useful for selecting patient cohorts benefitting
from immunotherapy.

ADENOSINE RECEPTOR 2B EXPRESSION PLAYS AN IMPORTANT ROLE IN THE TUMOR

MICROENVIRONMENT
Four subtypes of G-protein - coupled adenosine receptors exist, designated Adora1 (A1R), Adora2a, (A2AR),
Adora2b (A2BR), or Adora3 (A3R), and are classified according to utilization of pertussis toxin - sensitive
[19]
(A1 and A3) or - insensitive (A2A and A2B) pathways . In the tumor microenvironment, many cell types
[20]
express A2BR, especially under hypoxic conditions [Figure 1] . In neutrophils A1R has a higher affinity
for adenosine compared to A2AR or A2BR, and therefore at earlier stages of inflammation, lower local
concentrations of adenosine promoted neutrophil recruitment, while later high concentrations of adenosine
[21]
limit neutrophil recruitment through action of A2AR or A2BR . In dendritic cells (DCs), although
other adenosine receptors are expressed, A2BR mediates the differentiation of DCs that behave unlike
myeloid DCs as they display impaired allostimulatory activity and express high levels of angiogenic, pro-
inflammatory, immune suppressor and tolerogenic factors, including VEGF, IL-8, IL-6, IL-10, COX-2, TGF-b
[22]
and IDO. Furthermore, A2BR-mediated differentiation of DCs promoted lung tumors in mice . Human