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Page 753 Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63

Figure 1. Adenosine’s pleiotropic effects on immune cells. ADO facilitates the evasion of tumor cells from immune detection by
restricting the activity of T cells, DCs, NK cells, macrophages, and neutrophils. Concurrently, adenosine amplifies the functionality of
immunosuppressive cell types like MDSCs and Tregs. ADO: Adenosine; A2AR: A2A receptors; A2BR: A2B receptors; DCs: dendritic
cells; MDSCs: myeloid-derived suppressor cells; NK: natural killer; TNFα: tumor necrosis factor-alpha; Tregs: regulatory T cells; VEGF:
vascular endothelial growth factor.

myeloid precursors. Common monocyte precursors differentiate into a third major subtype of DCs .
[80]
Classical DCs have two major states: type 1 and type 2 (cDC1 and cDC2). cDC1 acts to recognize apoptotic
and necrotic cell debris presented on its MHC-I receptors to activate CD8+ effector T cells. Their function
helps to drive an antitumor response within the TME . cDC2 are more heterogenous than cDC1 cells in
[75]
tumors but are believed to play a role in recognizing exogenous tumor antigens and presenting them to
CD4+ T cells on MHC-II . Within cDC2 populations, there are two further subtypes: anti-inflammatory
[81]
(cDC2A) and proinflammatory (cDC2B). Classical DCs are now emerging as a potential target for PD-1/
PD-L1 immune checkpoint blockade. It has been demonstrated that the proper functioning of checkpoint
blockade requires cis interactions with CD80 and PD-L1, as well as PD-1 and PD-L1, between T cells and
the DCs [82,83] .

DCs that have differentiated during exposure to ADO display diminished activity. Moreover, these DCs
express high levels of angiogenic, immunosuppressive, proinflammatory, and tolerogenic factors, such as
cyclooxygenase-2 (COX-2), indoleamine 2,3-dioxygenase (IDO), interleukin-6 (IL-6), interleukin-8 (IL-8),
IL-10, TGF-β, and VEGF [84,85] . These DCs depend on the upregulation of A2BR when producing these
factors to promote ongoing tumor growth and increased angiogenesis for metastasis . As a result, blocking
[85]
A2BR can preserve the activity of DCs to present neoantigens to T cells, thereby facilitating the process of
tumor cell destruction.

NK cells
NKs are derived from CD34+ hematopoietic stem cell progenitors in bone marrow. These cells kill targets
that express either no or extremely low MHC-I on their surface [86,87] . NK cells have a specific killer
immunoglobulin-like receptor (KIR) on their surface that recognizes MHC-I molecules. When the KIRs
recognize MHC-I in self-cells, NK cells are downregulated to prevent an immune response [86,88,89] . Tumor
cells tend to have low MHC-I, which can stimulate suppressed NK cells to become activated . NK cells
[90]
often recognize specific cancer ligands upregulated within tumors, such as MHC-I polypeptide-related