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Funder: Dr. Arnold U. und Susanne Huggenberger-Bischoff Stiftung zur Krebsforschung (Huggenberger-Bischoff Foundationfor Cancer Research); doi: https://doi.org/10.13039/501100007878, Funder: Krebsliga Beider Basel (Cancer League of Basel-City and Basel-Country); doi: https://doi.org/10.13039/501100006069, Funder: Krebsliga Schweiz (Ligue Suisse Contre le Cancer); doi: https://doi.org/10.13039/501100004361, Funder: Swiss Personalized Health Network (Swiss Personalized Oncology driver project) Medical Faculty and Department of Surgery of the University Hospital Basel, Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.

Tumor-infiltrating dendritic cells (DCs) correlate with effective anticancer immunity and improved responsiveness to anti-PD-1 checkpoint immunotherapy. However, the drivers of DC expansion and intratumoral accumulation are ill-defined. We found that interleukin-2 (IL-2) stimulated DC formation through innate and adaptive lymphoid cells in mice and humans, and this increase in DCs improved anticancer immunity. Administration of IL-2 to humans within a clinical trial and of IL-2 receptor (IL-2R)-biased IL-2 to mice resulted in pronounced expansion of type 1 DCs, including migratory and cross-presenting subsets, and type 2 DCs, although neither DC precursors nor mature DCs had functional IL-2Rs. In mechanistic studies, IL-2 signals stimulated innate lymphoid cells, natural killer cells, and T cells to synthesize the cytokines FLT3L, CSF-2, and TNF. These cytokines redundantly caused DC expansion and activation, which resulted in improved antigen processing and correlated with favorable anticancer responses in mice and patients. Thus, IL-2 immunotherapy-mediated stimulation of DCs contributes to anticancer immunity by rendering tumors more immunogenic.

Background Acute chest pain is a frequent reason to attend an emergency room, and various instruments for calculating the probability of an acute coronary syndrome exist. Objective To assess the safety and efficiency of all available instruments investigated in sample validation studies. Methods A systematic review was conducted. Studies were identified describing the development of instruments and all subsequent validations in electronic databases and reference lists of included studies. Inclusion was screened for, full papers checked and data extracted on salient clinical features, performance characteristics and quality in duplicate. Results Of 20 derivation studies, 10 were at least validated once in 14 validations including 26 488 patients. One study by Selker and colleagues was validated in six new patient series and studies by Goldman et al and the Kennedy et al were both validated in three new patient series. All other studies were validated less than three times. In four out of six validations of the Selker et al study, the sensitivity of the prediction rule was 98% or higher. The corresponding values for specificity ranged from 4% to 34%. All remaining prediction rules showed sensitivity values below 95% in all validations. Conclusions No instrument assisting clinicians in the diagnostic investigation of patients with suspected acute coronary syndrome consistently fulfils the safety requirements of clinicians.