Unlocking the Adenosine Receptor Mechanism of the Tumour Immune Microenvironment

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Jul 12

PMID 38994361

Authors

Yecheng Han

Chenshuang Dong

Mingwang Hu

Xinmiao Wang

Guiling Wang

Affiliations

Soon will be listed here.

Abstract

The suppressive tumour microenvironment significantly hinders the efficacy of immunotherapy in treating solid tumors. In this context, stromal cells, such as tumour-associated fibroblasts, undergo changes that include an increase in the number and function of immunosuppressive cells. Adenosine, a factor that promotes tumour growth, is produced from ATP breakdown and is markedly elevated in the tumour microenvironment. It acts through specific binding to adenosine receptors, with A2A and A2B adenosine receptor being primary drivers of immunosuppression. This paper presents the roles of various adenosine receptors in different tumour microenvironments. This review focus on the function of adenosine receptors in the stromal cells and non-cellular components of the tumour microenvironment. Additionally, we summarize and discuss recent advances and potential trends in using adenosine receptor antagonists combined with immunotherapy.

Citing Articles

Purine metabolism-associated key genes depict the immune landscape in gout patients.

Li L, Wang H, Xiao L, Lai W Discov Oncol. 2025; 16(1):193.

PMID: 39960566 PMC: 11832965. DOI: 10.1007/s12672-025-01956-y.

Neoantigen mRNA vaccines and AA receptor antagonism: A strategy to enhance T cell immunity.

Imani S, Jabbarzadeh Kaboli P, Babaeizad A, Maghsoudloo M Hum Vaccin Immunother. 2025; 21(1):2458936.

PMID: 39882781 PMC: 11784654. DOI: 10.1080/21645515.2025.2458936.

Tumor Microenvironment Drives the Cross-Talk Between Co-Stimulatory and Inhibitory Molecules in Tumor-Infiltrating Lymphocytes: Implications for Optimizing Immunotherapy Outcomes.

Franzese O Int J Mol Sci. 2024; 25(23).

PMID: 39684559 PMC: 11641238. DOI: 10.3390/ijms252312848.

References

Mamdani H, Matosevic S, Khalid A, Durm G, Jalal S . Immunotherapy in Lung Cancer: Current Landscape and Future Directions. Front Immunol. 2022; 13:823618. PMC: 8864096. DOI: 10.3389/fimmu.2022.823618. View

Bai H, Zhang Z, Liu L, Wang X, Song X, Gao L . Activation of adenosine A3 receptor attenuates progression of osteoarthritis through inhibiting the NLRP3/caspase-1/GSDMD induced signalling. J Cell Mol Med. 2022; 26(15):4230-4243. PMC: 9344816. DOI: 10.1111/jcmm.17438. View

Kruger-Genge A, Blocki A, Franke R, Jung F . Vascular Endothelial Cell Biology: An Update. Int J Mol Sci. 2019; 20(18). PMC: 6769656. DOI: 10.3390/ijms20184411. View

Merighi S, Simioni C, Gessi S, Varani K, Mirandola P, Aghazadeh Tabrizi M . A(2B) and A(3) adenosine receptors modulate vascular endothelial growth factor and interleukin-8 expression in human melanoma cells treated with etoposide and doxorubicin. Neoplasia. 2009; 11(10):1064-73. PMC: 2745672. DOI: 10.1593/neo.09768. View

Christofi F, Zhang H, Yu J, Guzman J, Xue J, Kim M . Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. J Comp Neurol. 2001; 439(1):46-64. DOI: 10.1002/cne.1334. View

Tay A, Prieto-Diaz R, Neo S, Tong L, Chen X, Carannante V . A adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models. J Immunother Cancer. 2022; 10(5). PMC: 9115112. DOI: 10.1136/jitc-2022-004592. View

Bai R, Li Y, Jian L, Yang Y, Zhao L, Wei M . The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies. Mol Cancer. 2022; 21(1):177. PMC: 9454207. DOI: 10.1186/s12943-022-01645-2. View

Li X, Zhang Y, Walana W, Zhao F, Li F, Luo F . GDC-0941 and CXCL8 (3-72) K11R/G31P combination therapy confers enhanced efficacy against breast cancer. Future Oncol. 2020; 16(14):911-921. DOI: 10.2217/fon-2020-0035. View

Gessi S, Bencivenni S, Battistello E, Vincenzi F, Colotta V, Catarzi D . Inhibition of A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455. Front Pharmacol. 2017; 8:888. PMC: 5716981. DOI: 10.3389/fphar.2017.00888. View

10.

Tian D, Li J, Zou L, Lin M, Shi X, Hu Y . Adenosine A1 Receptor Deficiency Aggravates Extracellular Matrix Accumulation in Diabetic Nephropathy through Disturbance of Peritubular Microenvironment. J Diabetes Res. 2021; 2021:5584871. PMC: 8523293. DOI: 10.1155/2021/5584871. View

11.

Fishman P, Stemmer S, Bareket-Samish A, Silverman M, Kerns W . Targeting the A3 adenosine receptor to treat hepatocellular carcinoma: anti-cancer and hepatoprotective effects. Purinergic Signal. 2023; 19(3):513-522. PMC: 10539266. DOI: 10.1007/s11302-023-09925-2. View

12.

Torres-Pineda D, Mora-Garcia M, Garcia-Rocha R, Hernandez-Montes J, Weiss-Steider B, Montesinos-Montesinos J . Corrigendum to "Adenosine augments the production of IL-10 in cervical cancer cells through interaction with the A2B adenosine receptor, resulting in protection against the activity of cytotoxic T cells" [Cytokine 130 (2020) 155082]. Cytokine. 2020; 133:155110. DOI: 10.1016/j.cyto.2020.155110. View

13.

Pinter A, Hevesi Z, Zahola P, Alpar A, Hanics J . Chondroitin sulfate proteoglycan-5 forms perisynaptic matrix assemblies in the adult rat cortex. Cell Signal. 2020; 74:109710. DOI: 10.1016/j.cellsig.2020.109710. View

14.

Kamai T, Kijima T, Tsuzuki T, Nukui A, Abe H, Arai K . Increased expression of adenosine 2A receptors in metastatic renal cell carcinoma is associated with poorer response to anti-vascular endothelial growth factor agents and anti-PD-1/Anti-CTLA4 antibodies and shorter survival. Cancer Immunol Immunother. 2021; 70(7):2009-2021. PMC: 8195893. DOI: 10.1007/s00262-020-02843-x. View

15.

Feng W, Song Y, Chen C, Lu Z, Zhang Y . Stimulation of adenosine A(2B) receptors induces interleukin-6 secretion in cardiac fibroblasts via the PKC-delta-P38 signalling pathway. Br J Pharmacol. 2010; 159(8):1598-607. PMC: 2925484. DOI: 10.1111/j.1476-5381.2009.00558.x. View

16.

Zeynali P, Jazi M, Asadi J, Jafari S . A1 adenosine receptor antagonist induces cell apoptosis in KYSE-30 and YM-1 esophageal cancer cell lines. Biomedicine (Taipei). 2023; 13(1):54-61. PMC: 10166249. DOI: 10.37796/2211-8039.1394. View

17.

Bastid J, Regairaz A, Bonnefoy N, Dejou C, Giustiniani J, Laheurte C . Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity. Cancer Immunol Res. 2014; 3(3):254-65. DOI: 10.1158/2326-6066.CIR-14-0018. View

18.

de la Cruz-Lopez K, Castro-Munoz L, Reyes-Hernandez D, Garcia-Carranca A, Manzo-Merino J . Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches. Front Oncol. 2019; 9:1143. PMC: 6839026. DOI: 10.3389/fonc.2019.01143. View

19.

Antonioli L, Fornai M, Blandizzi C, Pacher P, Hasko G . Adenosine signaling and the immune system: When a lot could be too much. Immunol Lett. 2018; 205:9-15. DOI: 10.1016/j.imlet.2018.04.006. View

20.

Happe H, Bylund D, Murrin L . Alpha-2 adrenergic receptor functional coupling to G proteins in rat brain during postnatal development. J Pharmacol Exp Ther. 1999; 288(3):1134-42. View