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Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63 Page 752

CD73 within the TME leads to an upsurge in MDSCs and Tregs .
[59]
The influence of adenosine receptor expression in key immune cells
Innate immunity: the role of adenosine receptors in macrophages, dendritic cells, and natural killer cells
Innate immunity plays a critical role in the body’s defense against cancer by providing the first line of
protection against malignant cells [Figure 1]. This system, comprising various immune cells such as NKs,
TAMs, DCs, and soluble factors like cytokines and chemokines, acts to identify and eliminate transformed
cells. Recent studies have highlighted the dynamic interplay between innate immunity and cancer
progression, shedding light on the delicate balance between tumor-promoting and tumor-suppressing
functions of the innate immune system. An essential aspect of the innate immune system’s interaction with
cancer cells involves the A2BR, which modulates immune cell functions and significantly impacts the
balance between tumor-promoting and tumor-suppressing activities.

Tumor-associated macrophages
TAMs exhibit substantial plasticity that can play a part in tumor progression and drug resistance . The two
[66]
main classes of TAMs within the TME are activated M1 and alternatively activated M2 . M1 is known to
[67]
be the proinflammatory subset within the tumor, while M2 is considered to be suppressive. However, the
classes are not static; the cells can change their state based on the cytokines present. There are also subsets of
M2 within the TME, and each class plays a role in tumor formation and progression [67,68] .

The TME regulates M1 and M2 macrophages to regulate the immune response to tumors. TAM precursors
are derived from embryogenic or bone marrow-derived monocytes . TAMs tend to differentiate primarily
[66]
into M2-like phenotypes. These cells express high levels of VEGF (pro-angiogenic), mannose receptor
(CD206), and scavenger receptor (CD163). They release suppressive cytokines such as IL-10 and promote
immunosuppression within the tumor. M1 plays a key role in vaso-proliferation through the secretion of
inflammatory cytokines such as IL-6, IL-8, TNF-α, and IL-1β [67,69,70] . The presence of TAMs with high levels
of IL-1β within the TME contributes to neovascularization and is a predictor .
[69]
Apoptotic cells phagocytosed by TAMs (aka efferocytosis) release ATPs into the extracellular space in
tissues . ATP derivatives, specifically ADO, affect the immune activation of TAM through ADO
[71]
receptors [71-73] . The A2BR is upregulated on TAMs in response to interferon-gamma (IFN-γ). When
activated, A2BR suppresses the production of TNFα in infiltrating TAMs, inhibiting their capacity to secrete
cytokines that are crucial for antitumor immunity. This process ultimately promotes tumor growth .
[71]
Dendritic cells
DCs are important APCs that present antigens to T cells on MHC proteins. T cells that recognize self-
proteins abundant in tumors do not survive selection in the thymus. Intra-tumoral injections of DCs that
initiate CD8+ T cell activation have been used to increase responses to immune checkpoint blockade
immunotherapies [74-76] . Damage-associated molecular patterns (DAMPs) are used to determine if an
immune response needs to be stimulated or if there is immune tolerance to that antigen [74,77] . DAMPs
initiate a CD8+ T cell response within tumors but can also help re-prime effector CD8+ T cells to continue
the adaptive immune response. However, when tumor cells overcome immune surveillance, DCs may have
altered antigen processing and defective T cell activation .
[78]

Within the TME, there are numerous subsets of DCs along with migratory/tissue-resident DCs . Classical
[79]
DCs are derived from common myeloid progenitors that differentiate into common DC progenitors.
Plasmacytoid DCs (pDC) are believed to be derived from lymphoid cells but can also be derived from