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Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Interaction with aqueous phase dissolved organic matter (DOM) can alter the fate of trace organic contaminants of emerging concern once they enter the water cycle. In order to probe possible DOM binding mechanisms and their consequences for contaminant detection and quantification in natural waters, a set of laboratory experiments was conducted with aqueous solutions containing various operationally-defined "hydrophilic" and "hydrophobic" freshwater DOM fractions isolated by resin adsorption techniques from reference Suwannee River natural organic matter (SROM). Per unit mass of SROM carbon, hydrophobic acids (HoA) comprised the largest C fraction (0.63±0.029), followed by hydrophilic-neutrals (HiN, 0.11±0.01) and acids (HiA, 0.09±0.017). Aqueous solutions comprising 8mgL(-1) DOC of each SROM fraction were spiked with a concentration range (10-1000μgL(-1)) of bisphenol A (BPA), carbamazepine (CBZ), or ibuprofen (IBU) as model target compounds in 24mM NH4HCO3 background electrolyte at pH 7.4. Contaminant interaction with the SROM fractions was probed using fluorescence spectroscopy, and effects on quantitative analysis of the target compounds were measured using direct aqueous-injection liquid chromatography tandem mass spectrometry (LC-MS/MS). Total quenching was greater for the hydrophilic fractions of SROM and associations were principally with protein-like and fulvic acid-like constituents. Whereas LC-MS/MS recoveries indicated relatively weak interactions with most SROM factions, an important exception was the HiA fraction, which diminished recovery of CBZ and IBU by ca. 30% and 70%, respectively, indicating relatively strong molecular interactions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)