Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers, in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibiting the † To whom correspondence should be addressed. david.tuveson@cancer.org.uk.

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oxygen deficiency which began i n the late Barremian. This peak can be recognized either from organic carbon Normal marine deposition i n the early Aptian was in-contents or from intervals barren of calcareous plankton; terrupted by a n episode of ocean-wide dysoxialanoxia. i n most places it lies within the lower Aptian Globigeri-This event is recorded by the occurrence of organic car-nelloides blowi foraminiferal Zone and the Chiastozygus bon-rich sediments i n land sections from Europe and Deep litterarius nannofossil Zone (Conusphaera rothii Sub-Sea Drilling Project (DSDP)/Ocean Drilling Program zone) and occurred shortly after magnetic Chron CMO. (ODP) sites i n the North and South Atlantic, Indian and T h e dysoxiclanoxic interval affected sites i n a wide range Pacific Ocean Basins. T o elucidate the origin, and spatial o f oceanic paleoenuironments. Nannofossil assemblage and temporal relationships of these carbonaceous sedi-data indicate highly variable fertility during this interval ments, we have conducted a n integrated biostratigraphic, and suggest that no single model can account for the lithostratigraphic and geochemical investigation of four-origin of all organic carbon-rich horizons. These data inteen sections from a range of geographic and oceano-dicate that peak oxygen deficiency corresponded to a graphic settings. Based on the resulting high-resolution, highly eutrophic interval but less intense dysoxic/anoxic integrated foraminiferal and nannofossil biostratigraphy, periods were characterized by oligotrophic conditions. T h e it appears that most locations were characterized by a late Barremian to early Aptian was a time of evolutionary relatively brief interval of peak dysoxialanoxia (less than radiation i n both planktonic foraminifers and calcareous a million years i n duration), i n the midst of a longer nannofossils, no significant changes i n speciation rates (approximately 2-3 million year) interval of intermittent are associated with the oxygen-deficient interval itself. T h e extinction of one of the dominant Early Cretaceous nannoplankton species, Nannoconus steinmannii may be related to events which led to dysoxialanoxia including * Deceased. periodically higher fertility. Tectonovolcanic events such

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Cancer immunotherapy has entered in a new era with the development of first-generation immune checkpoint inhibitors targeting the PD1/PD-L1 and CTLA-4 pathways. In this context, considerable research effort is being deployed to find the next generation of cancer immunotherapeutics. The CD73-adenosine axis constitutes one of the most promising pathways in immuno-oncology. We and others have demonstrated the immunosuppressive role of CD73-adenosine in cancer and established proof-of-concept that the targeted blockade of CD73 or adenosine receptors could effectively promote anti-tumor immunity and enhance the activity of first-generation immune checkpoint blockers. With Phase I clinical trials now underway evaluating anti-CD73 or anti-A2A therapies in cancer patients, we here discuss the fundamental, preclinical and clinical findings related to the role of the CD73-adenosinergic pathway in tumor immunity.

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With the coming of age of cancer immunotherapy, the search for new therapeutic targets has led to the identification of immunosuppressive adenosine as an important regulator of antitumor immunity. This resulted in the development of selective inhibitors targeting various components of the adenosinergic pathway, including small molecules antagonists targeting the high affinity A2A adenosine receptor and low affinity A2B receptor, therapeutic monoclonal antibodies (mAbs) and small molecules targeting CD73 and therapeutic mAbs targeting CD39. As each regulator of the adenosinergic pathway present non-overlapping biologic functions, a better understanding of the mechanisms of action of each targeted approach should accelerate clinical translation and improve rational design of combination treatments. In this review, we discuss the potential mechanisms-of-action of anti-CD39 cancer therapy and potential toxicities that may emerge from sustained CD39 inhibition. Caution should be taken, however, in extrapolating data from gene-targeted mice to patients treated with blocking anti-CD39 agents. As phase I clinical trials are now underway, further insights into the mechanism of action and potential adverse events associated with anti-CD39 therapy are anticipated in coming years.