Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses ...remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.
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•Kinase PERK in melanoma cells restricts protective tumor-specific T cell immunity•PERK targeting drives immunogenic melanoma cell death via SEC61β-linked paraptosis•PERK-null tumors promote the expansion of immune competent monocyte-derived DCs•Stroma-originated type I IFN reprograms myelopoiesis in PERK-null tumors via STAT1
How adaptation to endoplasmic reticulum (ER) stress in cancer cells modulates anti-tumor immunity remains elusive. Mandula et al. demonstrate that elimination of the ER stress-related kinase, PERK, in melanoma cells activates protective T cell responses through paraptosis-mediated immunogenic cell death, which primes expansion of monocytic-lineage inflammatory DCs via type-I IFN-STAT1.
We calculate the two-loop contributions to the electric dipole moments of the electron and the neutron mediated by charged Higgs in a generic supersymmetric theories. The new contributions are ...originated from the potential CP violation in the trilinear couplings of the charged Higgs bosons to the scalar-top or the scalar-bottom quarks. These couplings did not receive stringent constraints directly. We find observable effects for a sizable portion of the parameter space related to the third generation scalar-quarks in the minimal supersymmetric standard model.
Every cell in the human body has a unique set of somatic mutations, but it remains difficult to comprehensively genotype an individual cell
. Here we describe ways to overcome this obstacle in the ...context of normal human skin, thus offering a glimpse into the genomic landscapes of individual melanocytes from human skin. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, melanocytes from chronically sun-exposed skin (for example, the face) had a lower mutation burden than melanocytes from intermittently sun-exposed skin (for example, the back). Melanocytes located adjacent to a skin cancer had higher mutation burdens than melanocytes from donors without skin cancer, implying that the mutation burden of normal skin can be used to measure cumulative sun damage and risk of skin cancer. Moreover, melanocytes from healthy skin commonly contained pathogenic mutations, although these mutations tended to be weakly oncogenic, probably explaining why they did not give rise to discernible lesions. Phylogenetic analyses identified groups of related melanocytes, suggesting that melanocytes spread throughout skin as fields of clonally related cells that are invisible to the naked eye. Overall, our results uncover the genomic landscapes of individual melanocytes, providing key insights into the causes and origins of melanoma.
Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic ...development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 ...trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13
CH25H
IL-21
PD-1
CD4
T helper cells ("CXCL13
T
") and Granzyme K
PD-1
effector-like CD8
T cells, whereas terminally exhausted CD39
TOX
PD-1
CD8
T cells dominated in nonresponders. CD4
and CD8
T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1
TCF-1
(Progenitor-exhausted) CD8
T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8
T cell differentiation occurs upon ICB. We found that these Progenitor CD8
T cells interact with CXCL13
T
within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13
T
control the differentiation of tumor-specific Progenitor exhasuted CD8
T cells following ICB.
Uveal melanoma is a clinically distinct and particularly lethal subtype of melanoma originating from melanocytes in the eye. Here, we performed multi-region DNA sequencing of primary uveal melanomas ...and their matched metastases from 35 patients. We observed previously unknown driver mutations and established the order in which these and known driver mutations undergo selection. Metastases had genomic alterations distinct from their primary tumors; metastatic dissemination sometimes occurred early during the development of the primary tumor. Our study offers new insights into the genetics and evolution of this melanoma subtype, providing potential biomarkers for progression and therapy.
Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited ...in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
There is lack of validated methods for quantifying the size of pleural effusion from standard transthoracic (TTE) windows. The purpose of this study is to determine whether pleural effusion ...(Peff) measured from routine two-dimensional (2D) TTE views correlate with chest radiograph (CXR).
Materials and methods
We retrospectively identified all inpatients who underwent a TTE and CXR within 2 days in a large tertiary care center. Peff was measured on TTE from parasternal long axis (PLAX), apical four-chamber (A4C), and subcostal views and on CXR. Logistic regression models were used determine optimal cut points to predict moderate or greater Peff.
Results
In 200 patients (mean age 69.3 ± 14.3 years, 49.5% female), we found statistically significant associations between Peff size assessed by all TTE views and CXR, with weak to moderate correlation (PLAX length: 0.21 (95% CI 0.05, 0.35); PLAX depth: 0.21 (95% CI 0.05, 0.35); A4C left: 0.31 (95% CI 0.13, 0.46); A4C right: 0.39 (95% CI 0.17, 0.57); subcostal: 0.38 (95% CI 0.07, 0.61). The best TTE thresholds for predicting moderate or greater left-sided Peff on CXR was PLAX length left > = 8.6 cm (sensitivity 78%, specificity 54%, PPV 26%, and NPV 92%). The best TTE thresholds for predicting moderate or greater right-sided Peff on CXR was A4C right > = 2.6 cm (sensitivity 87%, specificity 60%, PPV 37%, and NPV 94%).
Conclusions
We identified statistically significant associations with Peff size measured on TTE and CXR. The predictive ability of TTE to identify moderate or large pleural effusion is limited.
Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive ...vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.
Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire ...samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.
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•Deep evolutionary roots of individual GBMs suggest tumor-wide therapeutic targets•Whole-tumor transcriptome and chromatin analysis reveals divergent cells of origin•3D analysis depicts GBM and microenvironmental programs with regional specificity•An interactive 3D platform enables whole-tumor analysis of user-selected GBM features
An integrative 3D spatial analysis provides a whole-tumor perspective on human glioblastoma, mapping out regional specificity in tumor and microenvironment programs while highlighting tumor-wide features as promising targets for future therapeutic development.
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