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Journal For Immunotherapy of Cancer Jun 2024Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1)...
Exploring the predictive potential of programmed death ligand 1 expression in healthy organs and lymph nodes as measured by F-BMS986-192 PET: pooled analysis of data from four solid tumor types.
INTRODUCTION
Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events.
METHODS
Four F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV), lymph node SUV) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted.
RESULTS
Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUV 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUV 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUV 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity.
CONCLUSION
PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer.
Topics: Humans; B7-H1 Antigen; Lymph Nodes; Positron-Emission Tomography; Male; Female; Neoplasms; Immune Checkpoint Inhibitors; Middle Aged; Aged
PubMed: 38886117
DOI: 10.1136/jitc-2024-008899 -
Journal For Immunotherapy of Cancer Jun 2024Cancer/testis antigens (CTAs) are widely expressed in melanoma and lung cancer, emerging as promising targets for vaccination strategies and T-cell-based therapies in...
Cancer/testis antigens (CTAs) are widely expressed in melanoma and lung cancer, emerging as promising targets for vaccination strategies and T-cell-based therapies in these malignancies. Despite recognizing the essential impact of intratumoral heterogeneity on clinical responses to immunotherapy, our understanding of intratumoral heterogeneity in CTA expression has remained limited. We employed single-cell mRNA sequencing to delineate the CTA expression profiles of cancer cells in clinically derived melanoma and lung cancer samples. Our findings reveal a high degree of intratumoral transcriptional heterogeneity in CTA expression. In melanoma, every cell expressed at least one CTA. However, most individual CTAs, including the widely used therapeutic targets NY-ESO-1 and MAGE, were confined to subpopulations of cells and were uncoordinated in their expression, resulting in mosaics of cancer cells with diverse CTA profiles. Coordinated expression was observed, however, mainly among highly structurally and evolutionarily related CTA genes. Importantly, a minor subset of CTAs, including PRAME and several members of the GAGE and MAGE-A families, were homogenously expressed in melanomas, highlighting their potential as therapeutic targets. Extensive heterogeneity in CTA expression was also observed in lung cancer. However, the frequency of CTA-positive cancer cells was notably lower and homogenously expressed CTAs were only identified in one of five tumors in this cancer type. Our findings underscore the need for careful CTA target selection in immunotherapy development and clinical testing and offer a rational framework for identifying the most promising candidates.
Topics: Humans; Melanoma; Lung Neoplasms; Antigens, Neoplasm; Single-Cell Analysis; Male; Gene Expression Regulation, Neoplastic
PubMed: 38886115
DOI: 10.1136/jitc-2023-008759 -
Journal For Immunotherapy of Cancer Jun 2024Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and...
BACKGROUND
Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.
METHODS
Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS
EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS
MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
Topics: Animals; Mice; Humans; Matrix Metalloproteinase 9; Macrophages; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Receptors, Cell Surface; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Receptors, Antigen, T-Cell; Tumor Microenvironment; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 38886114
DOI: 10.1136/jitc-2023-008375 -
Physiological Reports Jun 2024Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by "an organ inside an organ," the gut microbiota. This... (Review)
Review
Although the liver is the largest metabolic organ in the body, it is not alone in functionality and is assisted by "an organ inside an organ," the gut microbiota. This review attempts to shed light on the partnership between the liver and the gut microbiota in the metabolism of macronutrients (i.e., proteins, carbohydrates, and lipids). All nutrients absorbed by the small intestines are delivered to the liver for further metabolism. Undigested food that enters the colon is metabolized further by the gut microbiota that produces secondary metabolites, which are absorbed into portal circulation and reach the liver. These microbiota-derived metabolites and co-metabolites include ammonia, hydrogen sulfide, short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide. Further, the liver produces several compounds, such as bile acids that can alter the gut microbial composition, which can in turn influence liver health. This review focuses on the metabolism of these microbiota metabolites and their influence on host physiology. Furthermore, the review briefly delineates the effect of the portosystemic shunt on the gut microbiota-liver axis, and current understanding of the treatments to target the gut microbiota-liver axis.
Topics: Gastrointestinal Microbiome; Humans; Liver; Animals; Nutrients; Bile Acids and Salts
PubMed: 38886098
DOI: 10.14814/phy2.16114 -
BMJ Open Diabetes Research & Care Jun 2024Oxidative stress is known to affect left ventricular functions negatively. There is a strong bidirectional connection between diabetes mellitus (DM) and oxidative... (Observational Study)
Observational Study
INTRODUCTION
Oxidative stress is known to affect left ventricular functions negatively. There is a strong bidirectional connection between diabetes mellitus (DM) and oxidative stress. In parallel, left ventricular dysfunction is observed more frequently, even in patients with DM without other risk factors. In this context, the objective of this study is to comparatively investigate the potential relationship between oxidative stress and subclinical left ventricular dysfunction (SCLVD) assessed by Myocardial Performance Index (MPI) in patients with and without DM.
RESEARCH DESIGN AND METHODS
The sample of this observational cross-sectional single-center study consisted of 151 patients who were evaluated for oxidative stress and SCLVD by tissue Doppler echocardiography. Patients' total oxidant status (TOS), total antioxidant status (TAS), and Oxidative Stress Index (OSI) values were calculated. The effects of oxidative stress and DM on MPI were analyzed.
RESULTS
There were 81 patients with DM (mean age: 46.17±10.33 years) and 70 healthy individuals (mean age: 45.72±9.04 years). Mean TOS and OSI values of the DM group were higher than healthy individuals (5.72±0.55 vs 5.31±0.50, p = <0.001; and 4.92±1.93 vs 1.79±0.39, p = <0.001; respectively). The mean TAS value of the DM group was significantly lower than the healthy group (1.21±0.40 vs 3.23±0.51, p = <0.001). There was a significant correlation between OSI and MPI mitral in the DM group (R 0.554, p = <0.001) but not in the healthy group (R -0.069, p=0.249).
CONCLUSIONS
Both oxidative stress and myocardial dysfunction were found to be more common in patients with DM. The study's findings indicated the negative effect of oxidative stress on myocardial functions. Accordingly, increased oxidative stress caused more significant deterioration in MPI in patients with DM compared with healthy individuals.
Topics: Humans; Oxidative Stress; Female; Male; Middle Aged; Ventricular Dysfunction, Left; Cross-Sectional Studies; Adult; Case-Control Studies; Antioxidants; Diabetes Mellitus; Biomarkers; Ventricular Function, Left; Echocardiography, Doppler; Diabetes Mellitus, Type 2; Prognosis; Follow-Up Studies
PubMed: 38886070
DOI: 10.1136/bmjdrc-2024-004153 -
Life Science Alliance Sep 2024Protein translation initiation is a conserved process involving many proteins acting in concert. The 13 subunit eukaryotic initiation factor 3 (eIF3) complex is...
Protein translation initiation is a conserved process involving many proteins acting in concert. The 13 subunit eukaryotic initiation factor 3 (eIF3) complex is essential for assembly of the pre-initiation complex that scans mRNA and positions ribosome at the initiation codon. We previously reported that a gain-of-function (gf) mutation affecting the G subunit of the eIF3 complex, , selectively modulates protein translation in the ventral cord cholinergic motor neurons. Here, through unbiased genetic suppressor screening, we identified that the gene mediates ()-dependent protein translation in motor neurons. LIN-66 is composed largely of low-complexity amino acid sequences with unknown functional domains. We combined bioinformatics analysis with in vivo functional dissection and identified a cold-shock domain in LIN-66 critical for its function. In cholinergic motor neurons, LIN-66 shows a close association with EIF-3.G in the cytoplasm. The low-complexity amino acid sequences of LIN-66 modulate its subcellular pattern. As cold-shock domains function broadly in RNA regulation, we propose that LIN-66 mediates stimulus-dependent protein translation by facilitating the interaction of mRNAs with EIF-3.G.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Eukaryotic Initiation Factor-3; Protein Biosynthesis; Motor Neurons; Mutation; RNA, Messenger; Amino Acid Sequence; Cold-Shock Response; Protein Domains
PubMed: 38886018
DOI: 10.26508/lsa.202402673 -
Life Science Alliance Sep 2024The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and...
The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.
Topics: Endoribonucleases; Phosphorylation; Protein Serine-Threonine Kinases; Humans; Endoplasmic Reticulum Stress; Protein Multimerization; Unfolded Protein Response; Endoplasmic Reticulum; Ribonucleases
PubMed: 38886017
DOI: 10.26508/lsa.202302562 -
ELife Jun 2024Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the...
Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.
Topics: Animals; Receptors, IgG; Mice; Myeloid Cells; Mice, Inbred C57BL; Cell Line, Tumor; Cytotoxicity, Immunologic; Immunoglobulin M; Signal Transduction; Macrophages; Neoplasms
PubMed: 38885133
DOI: 10.7554/eLife.91999 -
JMIR Research Protocols Jun 2024Vascular cognitive impairment (VCI) persistently impairs cognition and the ability to perform activities of daily living, seriously compromising patients' quality of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vascular cognitive impairment (VCI) persistently impairs cognition and the ability to perform activities of daily living, seriously compromising patients' quality of life. Previous studies have reported that disorders of serum iron metabolism and iron deposition in the brain can lead to inflammation, abnormal protein aggregation and degeneration, and massive neuronal apoptosis in the central nervous system, which in turn leads to a progressive decline in cognitive processes. Our previous clinical studies have found acupuncture to be a safe and effective intervention for treating VCI, but the specific mechanisms require further exploration.
OBJECTIVE
The objective of the trial is to evaluate the clinical efficacy of Tongdu Xingshen acupuncture and to investigate whether it can improve VCI by regulating brain iron deposition and body iron metabolism.
METHODS
In total, 42 patients with VCI and 21 healthy individuals will participate in this clinical trial. The 42 patients with VCI will be randomized into acupuncture and control groups, while the 21 healthy individuals will be in the healthy control group. Both the control and acupuncture groups will receive conventional medical treatment and cognitive rehabilitation training. In addition, the acupuncture group will receive electroacupuncture treatment with Tongdu Xingshen for 30 minutes each time, 6 times a week for 4 weeks. Meanwhile, the healthy control group will not receive any intervention. All 3 groups will undergo baseline assessments of brain iron deposition, serum iron metabolism, and neuropsychological tests after enrollment. The acupuncture and control groups will be evaluated again at the end of 4 weeks of treatment, as described earlier. By comparing neuropsychological test scores between groups, we will examine the efficacy of Tongdu Xingshen acupuncture in treating VCI. Additionally, we will test the correlations between neuropsychological test scores, brain iron deposition, and body iron metabolism indexes to explore the possible mechanisms of Tongdu Xingshen acupuncture in treating VCI.
RESULTS
Participants are currently being recruited. The first participant was enrolled in June 2023, which marked the official start of the experiment. As of the submission of the paper, there were 23 participants. The recruitment process is expected to continue until June 2025, at which point the processing and analysis of data will begin. As of May 15, 2024, up to 30 people have been enrolled in this clinical trial.
CONCLUSIONS
This study will provide data on the effects of Tongdu Xingshen acupuncture on cerebral iron deposition as well as somatic iron metabolism in patients with VCI. These results will help to prove whether Tongdu Xingshen acupuncture can improve VCI by regulating brain iron deposition and body iron metabolism, which will provide the clinical and theoretical basis for the wide application of acupuncture therapy in VCI rehabilitation.
TRIAL REGISTRATION
China Clinical Registration Agency ChiCTR2300072188; https://tinyurl.com/5fcydtkv.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
PRR1-10.2196/56484.
Topics: Humans; Acupuncture Therapy; Iron; Brain; Cognitive Dysfunction; Male; Female; Middle Aged; Aged; Adult
PubMed: 38885500
DOI: 10.2196/56484 -
Neurology(R) Neuroimmunology &... Jul 2024Kleine-Levin syndrome (KLS) is a rare recurrent hypersomnolence disorder associated with cognitive and behavioral disturbances, of unknown origin, but inflammatory...
OBJECTIVES
Kleine-Levin syndrome (KLS) is a rare recurrent hypersomnolence disorder associated with cognitive and behavioral disturbances, of unknown origin, but inflammatory mechanisms could be involved. We aimed to explore in vivo microglia activation using [F]DPA-714 PET imaging in patients with KLS compared with controls, and during symptomatic vs asymptomatic periods.
METHODS
Patients with KLS and controls underwent a standardized clinical evaluation and PET imaging, using a radiolabeled ligand specific to the 18 kDa translocator protein. Images were processed on the PMOD (peripheral module) interface using a standard uptake value (SUV). Five regions of interest (ROIs) were analyzed: hypothalamus, thalamus, frontal area, cerebellum, and whole brain. SUV ratios (SUVr) were calculated by normalizing SUV with cerebellum uptake.
RESULTS
Images of 17 consecutive patients with KLS (7 during episodes, 10 out of episodes) and 14 controls were analyzed. We found no SUV/SUVr difference between KLS and controls, between patients in and out episodes in all ROIs, and no correlation between SUVr and episode duration at the time of PET scan. No association was found between SUVr and sex, disease duration, or orexin levels.
DISCUSSION
Our findings do not support the presence of neuroinflammation in KLS. Further research is needed to identify relevant biomarkers in KLS.
Topics: Humans; Kleine-Levin Syndrome; Male; Positron-Emission Tomography; Female; Microglia; Adult; Young Adult; Adolescent; Brain; Middle Aged
PubMed: 38885456
DOI: 10.1212/NXI.0000000000200263