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The diverse T cell receptor (TCR) repertoire confers the ability to recognize an almost unlimited array of antigens. Characterization of antigen specificity of tumor-infiltrating lymphocytes (TILs) is key for understanding antitumor immunity and for guiding the development of effective immunotherapies. Here, we report a large-scale comprehensive examination of the TCR landscape of TILs across the spectrum of pediatric brain tumors, the leading cause of cancer-related mortality in children. We show that a T cell clonality index can inform patient prognosis, where more clonality is associated with more favorable outcomes. Moreover, TCR similarity groups’ assessment revealed patient clusters with defined human leukocyte antigen associations. Computational analysis of these clusters identified putative tumor antigens and peptides as targets for antitumor T cell immunity, which were functionally validated by T cell stimulation assays in vitro. Together, this study presents a framework for tumor antigen prediction based on in situ and in silico TIL TCR analyses. We propose that TCR-based investigations should inform tumor classification and precision immunotherapy development. 

Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors. 

Abstract Removal of biologically available nitrogen (N) by the microbially mediated processes denitrification and anaerobic ammonium oxidation (anammox) affects ecosystem N availability. Although few studies have examined temperature responses of denitrification and anammox, previous work suggests that denitrification could become more important than anammox in response to climate warming. To test this hypothesis, we determined whether temperature responses of denitrification and anammox differed in shelf and estuarine sediments from coastal Rhode Island over a seasonal cycle. The influence of temperature and organic C availability was further assessed in a 12‐week laboratory microcosm experiment. Temperature responses, as characterized by thermal optima (T_opt) and apparent activation energy (E_a), were determined by measuring potential rates of denitrification and anammox at 31 discrete temperatures ranging from 3 to 59 °C. With a few exceptions,T_optandE_aof denitrification and anammox did not differ in Rhode Island sediments over the seasonal cycle. In microcosm sediments,E_a was somewhat lower for anammox compared to denitrification across all treatments. However,T_opt did not differ between processes, and neither E_a nor T_opt changed with warming or carbon addition. Thus, the two processes behaved similarly in terms of temperature responses, and these responses were not influenced by warming. This led us to reject the hypothesis that anammox is more cold‐adapted than denitrification in our study system. Overall, our study suggests that temperature responses of both processes can be accurately modeled for temperate regions in the future using a single set of parameters, which are likely not to change over the next century as a result of predicted climate warming. We further conclude that climate warming will not directly alter the partitioning of N flow through anammox and denitrification.