Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. and studies demonstrate that CD38 inhibits CD8 T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8 T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. .

TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors.

Supercritical water desulfurization (SCWDS) has potential as a technique for removing sulfur from feedstocks such as heavy oil and bitumen. However, a fundamental understanding of SCWDS (such as the underlying chemical mechanisms, relative rates of desulfurization, and the role of SCW and hydrocarbons) is limited. In the present work, we have gained molecular-level insights into this process by measuring the kinetics of decomposition of a variety of organic sulfides in the presence of hydrocarbons and supercritical water in a continuously fed stirred-tank reactor (CSTR). The results are consistent with a free-radical mechanism, with hydrogen abstraction from the sulfide as the rate-determining step. The decomposition rates of the aliphatic and aromatic sulfides varied depending on their molecular structure, with conversions after 31 min at 400 °C ranging from less than 3% (our detection limits) to more than 90%. These differences in the reactivity correlate with the estimated heats of reaction for the critical hydrogen abstraction. The decomposition rates of the sulfides were affected by the presence of hydrocarbon carriers, with the rates being higher in the presence of alkanes than in the presence of toluene, as expected for a free-radical process. Product distributions and rates of radical-induced alkane cracking during this process were likewise affected by the presence of different sulfides. The decomposition of several different sulfides is consistent with 3 / 2 power kinetics, providing further evidence that the reaction proceeds via a radical mechanism. The knowledge developed in the current work provides a fundamental basis for further improvements in SCWDS.

Oxidative desulfurization (ODS) removes organic sulfur compounds from liquid transportation fuels (including diesel and jet fuels) in a two-step process: (1) chemical oxidation to form sulfones and (2) adsorption (or extraction) of the sulfones onto a polar adsorbent such as alumina. Continued development of ODS is limited in part by a lack of understanding of how different sulfur types in real fuels respond to its constituent oxidation and extraction steps. We treated two JP-8 jet fuels (described by here as 3773 and 4177, respectively) using the two-step ODS process. These two fuels had similar physical properties and hydrocarbon compositions but differing sulfur contents: the 3773 fuel was 720 ppm w , while that of the 4177 fuel sulfur content was 1400 ppm w . For the two-step ODS process, we used activated carbon-promoted performic acid as the oxidant and activated alumina as the adsorbent. The complete ODS treatment reduced the sulfur content of the 3773 fuel to a level below the detection limits of our total sulfur analyzer (40 ppm w ), implying >94% sulfur removal. However, ODS treatment reduced the sulfur content of the 4177 fuel to 350 ppm w , or 75% sulfur removal. To investigate this discrepancy at the molecular level, we targeted sulfur compounds in the stock and treated fuels using one-dimensional gas chromatography and comprehensive two-dimensional gas chromatography with both sulfur selective detection and time-of-flight mass spectrometry. Initially, the 4177 fuel was dominated by a suite of compounds identified as sulfides, disulfides, and thiophenes (SDT), whereas the 3773 fuel was dominated by its benzothiophene (BT) content. The SDT compounds were easily oxidized, but the corresponding sulfones were not efficiently removed using the alumina adsorbent. The BT compounds were more resistant to oxidation than the SDT compounds, but the oxidized BT compounds were more efficiently removed using the adsorbent than either the BT compounds or oxidized SDT compounds. Development of ODS technologies should account for the different responses of different sulfur compounds to the oxidation and adsorption treatments.

Genetics, Varian and Zai Labs. P. Jones reports serving as a consultant for Tvardi Therapeutics.T.P. Heffernan reports personal fees and stock ownership from Cullgen Inc. F. Meric-Bernstam reports receiving commercial research grants from Aileron Therapeutics Inc., Research.