Targeting the adenosine pathway reshapes a myeloid-dependent tumour microenvironment in pancreatic ductal adenocarcinoma. An opportunity for therapeutic intervention
Background: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor with less than 10% of patients surviving more than 5 years from the diagnosis. PDAC is considered relatively resistant to conventional therapies and recently lack of efficacy of immunotherapy has been shown for this aggressive malignancy. Recently a novel immunosuppressive pathway, called adenosine pathway, has been suggested to contribute to the ability of PDAC to evade the immune system and its resistance to immunotherapies (IOT) and cytotoxic treatments, by generating extracellular adenosine (eAdo) as a consequence of the conversion of a molecule of ATP by enzymes called CD39 and CD73. The stimulation of the adenosine receptors by extracellular adenosine on the immune cells has been shown to favour a pro-tumorigenic and tolerogenic microenvironment. Results: Using syngeneic, *in vivo* murine models of PDAC with differential immune infiltration and response to IOT and the KPC mouse model, CD39 and CD73 were shown to be highly expressed on tumour-infiltrating immune cells. The distribution of extracellular adenosine appeared heterogeneous in murine PDAC, with high concentrations in hypoxic areas, enriched for myeloid infiltration. M2 macrophages among other myeloid populations, highly expressed the Adora2a receptor, particularly in the IOT-resistant model. Targeting the adenosine pathway (Adoi) delayed tumour growth and reduced the occurrence of lung metastases in IOT-resistant tumours. Further, Adoi improved the efficacy of combinations of cytotoxic agents or immunotherapy. Genes related to immune modulation, hypoxia response and tumour stroma were downregulated following Adoi. Further tumour-infiltrating M2 macrophages were found reduced following Adoi. Finally, an adenosine-related gene dataset generated by RNAseq was shown to have similarities with the squamous subtype of PDAC identified by Bailey in humans (Bailey P. et al. 2016) and a specific adenosine signature was generated associating the adenosine pathway to a poorer prognosis in human PDAC. Conclusions: The formation of eAdo appears to favour the development of the immunosuppressive and pro-tumorigenic TME in PDAC, contributing to its resistance to conventional and novel therapies. The presence of the adenosine pathway in human PDAC seems to associate with biological features of aggressiveness and be related to a poorer prognosis. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the TME and improve response to therapy in patients with PDAC.
adenosine, immunotherapy, macrophages, pancreatic cancer, tumour microenvironment
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