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Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63 Page 754

sequence A (MICA), MICB, UL-16 binding proteins, complement factor P, and platelet-derived growth
factor DD [91-93] .

NK cells may have an important role in tumor immunosurveillance. In some cancers, such as colon cancer
and gastrointestinal stromal tumors, low NK cell expression is associated with poor outcomes [94,95] . NK cells
can also kill circulating tumor cells that are implicated in metastasis . Tumors may become resistant to NK
[96]
cell effects by suppressing immune cell activation. Like other immune cells, the hypoxic and low-nutrient
environment in tumors can decrease NK cell activation . Tumors increase the interactions of activating
[97]
ligands with their receptors on NK cells to stimulate later resistance to the cells. This increased stimulation
can suppress the NK cell function .
[98]

When NK cells are activated and encounter adenosine through the A2BR, it triggers the cyclic adenosine
monophosphate (cAMP) pathway. This activation subsequently blocks cytotoxic activity and cytokine
production, diminishing antitumor activity [99,100] . NK cells can also increase CD73 on their surface after
encountering mesenchymal stromal cells, thereby contributing to an increase in ADO and tumor
growth . This increase in ADO associated with high levels of A2AR contributes to suppressing NK
[101]
antitumor function [102,103] .

Adaptative immunity - the influence of adenosine receptors on t cell function
Adaptive immunity is the second line of defense in the immune system during infection or cancer. These
immune responses are cytotoxic to tumor cells. The main two tumor-infiltrating lymphocyte (TIL) cell
populations that mediate adaptive immunity are T cells (CD4+ and CD8+) and B cells. T cell infiltration
within tumors depends on the tumor chemokine profile and how easily immune cells can enter through the
tumor extracellular matrix. Over the last decade, improved methods have been developed to engineer T cells
to be better at avoiding cancer immunosuppression. These techniques have resulted in clinical trials of
blood-derived tumors and some sarcomas. Very little progress has been made for solid tumors. However,
targeting the A2AR on T cells may help overcome the difficulties of T cell immunotherapies in solid tumors.
Since ADO causes an increase in Tregs among infiltrating T cells, blocking A2AR can help maintain a high
amount of CD4+ T cells in solid tumors. Relative to T cells, B cells have very low levels of A2BR, and limited
studies have investigated its role in A2BR activation from ADO . A2AR are more abundant in human
[104]
than mouse B cells, but their role in immunotherapy is unknown.

T cells
T cells have been the main target of immunotherapy. CAR T cells and immune checkpoint inhibitors have
been used to enhance T cell-mediated tumor killing. Dangaj et al. demonstrated that CCL5 must be present
within the TME for TILs to enter solid tumors. The macrophages and DCs within the tumor also need to
produce CXCL9 to aid in T cell infiltration . Anti-PD-1 therapies have only shown limited success in solid
[105]
tumors. In metastatic head and neck squamous cell carcinoma, only 15% of patients responded to anti-PD-1
treatment, and very few responses have been seen in microsatellite-stable colorectal cancer [106,107] . Duhen
et al. discovered a subset of CD4+ T cells in tumors that are double positive for PD-1 and inducible
costimulator (ICOS) . These cells can have a tumor tissue-resident phenotype that allows them to
[106]
recognize both tumor antigens and neoantigens on MHC-II. CD8+ TILs, on the other hand, are more
heterogeneous in their response to tumor antigens . The presence of PD-1 and ICOS on CD4+ T cells
[108]
may work in conjunction with CD8+ T cells to stimulate a robust antitumor response.

Co-expression of CD39 and CD103 on CD8+ TIL within solid tumors has shown promise in targeting
tumor cells. CD8+ T cells that have high expression of CD39 and CD103 can be identified in both primary