IL-18 receptor marks functional CD8+ T cells in non-small cell lung cancer.
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ABSTRACT:
SUBMITTER: Timperi E
PROVIDER: S-EPMC5543928 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundStudies about CD8+ FOXP3+ T cells as a subtype of regulatory T cells (Treg cells) in non-small cell lung cancer (NSCLC) are few. Associations among the clinicopathologic factors of NSCLC and tumor-infiltrating lymphocytes (TILs) such as CD8+ FOXP3+ T cells, CD8+ T cells, FOXP3+ T cells and tumor PD-L1 expression are unclear.MethodsWe retrospectively enrolled 192 patients who underwent resections for NSCLC. We used tissue microarrays (TMA) with multiplex immunofluorescence and immunohistochemistry staining to evaluate the expression of CD8, FOXP3, cytokeratin, DAPI and PD-L1. We then used Wilcoxon test, Kaplan-Meier method, and Cox hazard proportion model to analyze their relationships with clinicopathologic factors and prognosis.ResultsDensity of tumor CD8+ FOXP3+ T cells was significant by univariate analysis, and positively associated with tumor CD8+ T cells and FOXP3+ T cells. Density of tumor CD8+ T cells was higher in lung adenocarcinoma (LUAD) than squamous cell carcinoma (LUSC), and was an independent prognostic factor for NSCLC. The density of tumor FOXP3+ T cells decreased with tumor size. Tumor PD-L1 expression was higher in LUSC than LUAD. Cox hazard proportion model analysis correlated being younger than 65 years, early TNM stage, early T stage, high tumor CD8+ T cell density, and adjuvant chemotherapy with longer overall survival.ConclusionInfiltration of CD8+ FOXP3+ T cells, CD8+ T cells, and FOXP3+ T cells is important in non-small cell lung cancer microenvironment, and needs to be investigated more.
| S-EPMC7270696 | biostudies-literature
Project description:Hypoxic tumors exhibit increased resistance to radiation, chemical, and immune therapies. 18F-fluoromisonidazole (18F-FMISO) PET is a noninvasive, quantitative imaging technique used to evaluate the magnitude and spatial distribution of tumor hypoxia. In this study, pharmacokinetic analysis (PKA) of 18F-FMISO dynamic PET extended to 3 h after injection is reported for the first time, to our knowledge, in stage III-IV non-small cell lung cancer (NSCLC) patients. Methods: Sixteen patients diagnosed with NSCLC underwent 2 PET/CT scans (1-3 d apart) before radiation therapy: a 3-min static 18 F-FDG and a dynamic 18F-FMISO scan lasting 168 ± 15 min. The latter data were acquired in 3 serial PET/CT dynamic imaging sessions, registered with each other and analyzed using pharmacokinetic modeling software. PKA was performed using a 2-tissue, 3-compartment irreversible model, and kinetic parameters were estimated for the volumes of interest determined using coregistered 18F-FDG images for both the volume of interest-averaged and the voxelwise time-activity curves for each patient's lesions, normal lung, and muscle. Results: We derived average values of 18F-FMISO kinetic parameters for NSCLC lesions as well as for normal lung and muscle. We also investigated the correlation between the trapping rate (k3) and delivery rate (K1), influx rate (Ki ) constants, and tissue-to-blood activity concentration ratios (TBRs) for all tissues. Lesions had trapping rates 1.6 times larger, on average, than those of normal lung and 4.4 times larger than those in muscle. Additionally, for almost all cases, k3 and Ki had a significant strong correlation for all tissue types. The TBR-k3 correlation was less straightforward, showing a moderate to strong correlation for only 41% of lesions. Finally, K1-k3 voxelwise correlations for tumors were varied, but negative for 76% of lesions, globally exhibiting a weak inverse relationship (average R = -0.23 ± 0.39). However, both normal tissue types exhibited significant positive correlations for more than 60% of patients, with 41% having moderate to strong correlations (R > 0.5). Conclusion: All lesions showed distinct 18F-FMISO uptake. Variable 18F-FMISO delivery was observed across lesions, as indicated by the variable values of the kinetic rate constant K1 Except for 3 cases, some degree of hypoxia was apparent in all lesions based on their nonzero k3 values.
| S-EPMC5450365 | biostudies-literature
Project description:Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8+ memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically 'record' the replicative history of different CD8+ T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T (TCM) cell pool is marked by a higher number of prior divisions than the effector memory T cell pool, owing to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single-cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the TCM compartment. Specifically, we demonstrate that lowly divided TCM cells display enriched expression of stem-cell-associated genes, exist in a relatively quiescent state, and are superior in eliciting a proliferative recall response upon activation. These data provide the first evidence that a stem-cell-like memory T cell pool that reconstitutes the CD8+ T cell effector pool upon reinfection is marked by prior quiescence.
| S-EPMC7612726 | biostudies-literature
Project description:BackgroundPredictive markers for treatment response and survival outcome have not been identified in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemoimmunotherapy. We aimed to evaluate whether imaging biomarkers of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and routinely assessed clinico-laboratory values were associated with clinical outcomes in patients with advanced NSCLC receiving pembrolizumab plus platinum-doublet chemotherapy as a first-line treatment.MethodsWe retrospectively enrolled 52 patients with advanced NSCLC who underwent baseline 18F-FDG PET/CT before treatment initiation. PET/CT parameters and clinico-laboratory variables, constituting the prognostic immunotherapy scoring system, were collected. Optimal cut-off values for PET/CT parameters were determined using the maximized log-rank test for progression-free survival (PFS). A multivariate prediction model was developed based on Cox models for PFS, and a scoring system was established based on hazard ratios of the predictive factors.ResultsDuring the median follow-up period of 16.7 months (95% confidence interval: 15.7-17.7 months), 43 (82.7%) and 31 (59.6%) patients experienced disease progression and death, respectively. Objective response was observed in 23 (44.2%) patients. In the multivariate analysis, maximum standardized uptake value, metabolic tumour volume2.5, total lesion glycolysis2.5, and bone marrow-to-liver uptake ratio from the PET/CT variables and neutrophil-to-lymphocyte ratio (NLR) from the clinico-laboratory variables were independently associated with PFS. The scoring system based on these independent predictive variables significantly predicted the treatment response, PFS, and overall survival.ConclusionPET/CT variables and NLR were useful biomarkers for predicting outcomes of patients with NSCLC receiving pembrolizumab and chemotherapy as a first-line treatment, suggesting their potential as effective markers for combined PD-1 blockade and chemotherapy.
| S-EPMC8753071 | biostudies-literature
Project description:PurposeThe aim of this study was to determine the relative abilities of compartment models to describe time-courses of 18 F-fluoromisonidazole (FMISO) uptake in tumor voxels of patients with non-small cell lung cancer (NSCLC) imaged using dynamic positron emission tomography. Also to use fits of the best-performing model to investigate changes in fitted rate-constants with distance from the tumor edge.MethodsReversible and irreversible two- and three-tissue compartment models were fitted to 24 662 individual voxel time activity curves (TACs) obtained from tumors in nine patients, each imaged twice. Descriptions of the TACs provided by the models were compared using the Akaike and Bayesian information criteria (AIC and BIC). Two different models (two- and three-tissue) were fitted to 30 measured voxel TACs to provide ground-truth TACs for a statistical simulation study. Appropriately scaled noise was added to each of the resulting ground-truth TACs, generating 1000 simulated noisy TACs for each ground-truth TAC. The simulation study was carried out to provide estimates of the accuracy and precision with which parameter values are determined, the estimates being obtained for both assumptions about the ground-truth kinetics. A BIC clustering technique was used to group the fitted rate-constants, taking into consideration the underlying uncertainties on the fitted rate-constants. Voxels were also categorized according to their distance from the tumor edge.ResultsFor uptake time-courses of individual voxels an irreversible two-tissue compartment model was found to be most precise. The simulation study indicated that this model had a one standard deviation precision of 39% for tumor fractional blood volumes and 37% for the FMISO binding rate-constant. Weighted means of fitted FMISO binding rate-constants of voxels in all tumors rose significantly with increasing distance from the tumor edge, whereas fitted fractional blood volumes fell significantly. When grouped using the BIC clustering, many centrally located voxels had high-fitted FMISO binding rate-constants and low rate-constants for tracer flow between the vasculature and tumor, both indicative of hypoxia. Nevertheless, many of these voxels had tumor-to-blood (TBR) values lower than the 1.4 level commonly expected for hypoxic tissues, possibly due to the low rate-constants for tracer flow between the vasculature and tumor cells in these voxels.ConclusionsTime-courses of FMISO uptake in NSCLC tumor voxels are best analyzed using an irreversible two-tissue compartment model, fits of which provide more precise parameter values than those of a three-tissue model. Changes in fitted model parameter values indicate that levels of hypoxia rise with increasing distance from tumor edges. The average FMISO binding rate-constant is higher for voxels in tumor centers than in the next tumor layer out, but the average value of the more simplistic TBR metric is lower in tumor centers. For both metrics, higher values might be considered indicative of hypoxia, and the mismatch in this case is likely to be due to poor perfusion at the tumor center. Kinetics analysis of dynamic PET images may therefore provide more accurate measures of the hypoxic status of such regions than the simpler TBR metric, a hypothesis we are presently exploring in a study of tumor imaging versus histopathology.
| S-EPMC5600259 | biostudies-literature
Project description:N-[18F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [18F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [18F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. The utility of PET in this context provides a non-invasive, quantifiable method to inform on the pharmacokinetics of an ALK-inhibitor such as crizotinib prior to a clinical trial, as well as during a trial in the event of acquired drug resistance.
| S-EPMC7357882 | biostudies-literature
Project description:AimTo investigate the diagnostic potential of and associations between tumor 18F-FDG uptake on PET imaging and cancer-associated weight loss.Methods774 non-small cell lung cancer (NSCLC) patients with pre-treatment PET evaluated between 2006 and 2014 were identified. Using the international validated definition of cachexia, the presence of clinically significant pretreatment cancer-associated weight loss (WL) was retrospectively determined. Maximum Standardized Uptake Value (SUVMax) of 18F-FDG was recorded and dichotomized based on 3 experimental cutpoints for survival analyses. Each SUVMax cutpoint prioritized either survival differences, total cohort comparison sample sizes, or sample size by stage. Patient outcomes and associations between SUVMax and cancer-associated weight loss were assessed by multivariate, categorical, and survival analyses.ResultsPatients were found to have an increased likelihood of having WL at diagnosis associated with increasing primary tumor SUVMax after controlling for potentially confounding patient and tumor characteristics on multivariate logistic regression (OR 1.038; 95% CI: 1.012, 1.064; P=0.0037). After stratifying the cohort by WL and dichotomized SUVMax, both factors were found to be relevant in predicting survival outcomes when the alternative variable was constant. Of note, the most striking survival differences contributed by WL status occurred in high SUVMax groups, where the presence of WL predicted a median survival time detriment of up to 10 months, significant regardless of cutpoint determination method applied to categorize high SUVMax patients. SUVMax classification was found to be most consistently relevant in both WL and no WL groups.ConclusionsThe significant positive association between significant pretreatment cancer-associated weight loss and primary tumor SUVMax underscores increased glucose uptake as a component of catabolic tumor phenotypes. This substantiates 18F-FDG PET analysis as a prospective tool for assessment of cancer-associated weight loss and corresponding survival outcomes. Furthermore, the survival differences observed between WL groups across multiple SUVMax classifications supports the importance of weight loss monitoring in oncologic workups. Weight loss in the setting of NSCLCs with higher metabolic activity as determined by 18F-FDG PET signal should encourage more aggressive and earlier palliative care interventions.
| S-EPMC9263563 | biostudies-literature
Project description:BackgroundSince tumor cells may escape from immune surveillance through the programmed cell death 1 (PD-1)/programmed death ligand (PD-L)1 axis, this study was designed in order to evaluate whether there is a correlation between the levels of PD-1+ and PD-L1+-expressing immune cells (ICs) and circulating tumor cells (CTCs) in patients with non-small cell lung cancer (NSCLC).Patients and methodsPeripheral blood was obtained from 37 chemotherapy-naïve patients with metastatic NSCLC before treatment. PD-1 and PD-L1 expression was evaluated (1) on ICs with anti-tumor function (CD4+ and CD8+ T-cells, B-cells, monocytes/dendritic cells) using flow cytometry, (2) on CTCs by immunofluorescence and (3) on cells from tumor tissues by immunohistochemistry. The levels of PD-1+ and PD-L1+-expressing ICs were correlated with progression-free survival (PFS).ResultsThe presence of PD-1+ CD8+ cells, with reduced interferon (IFN)-γ expression, but not other ICs, were positively correlated with PD-L1+ CTCs (p < 0.04). Increased percentages of PD-1+ CD8+ T-cells, were associated with a worse response to treatment (p = 0.032) and shorter PFS (p = 0.023) which, in multivariate analysis, was revealed as an independent predictor for decreased PFS [hazard ratio (HR): 4.1, p = 0.0007].ConclusionThe results of the current study, for first time, provide evidence for a possible interaction between ICs and CTCs in NSCLC patients via the PD-1/PD-L1 axis and strongly support that the levels of PD-1+ CD8+ in these patients may be of clinical relevance.
| S-EPMC6563396 | biostudies-literature
Project description:BackgroundAccumulating evidence showed that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Programmed Death Ligand 1 (PD-L1) is expressed in many cancer cell types, while its binding partner Programmed Death 1 (PD1) is expressed in activated T cells and antigen-presenting cells. Whereas, its dysregulation in the microenvironment is poorly understood. In the present study, we confirmed that evodiamine downregulates MUC1-C, resulting in modulating PD-L1 expression in non-small cell lung cancer (NSCLC).MethodsCell viability was measured by MTT assays. Apoptosis, cell cycle and surface PD-L1 expression on NSCLC cells were analyzed by flow cytometry. The expression of MUC1-C and PD-L1 mRNA was measured by real time RT-PCR methods. Protein expression was examined in evodiamine-treated NSCLC cells using immunoblotting or immunofluorescence assays. The effects of evodiamine treatment on NSCLC sensitivity towards T cells were investigated using human peripheral blood mononuclear cells and Jurkat, apoptosis and IL-2 secretion assays. Female H1975 xenograft nude mice were used to assess the effect of evodiamine on tumorigenesis in vivo. Lewis lung carcinoma model was used to investigate the therapeutic effects of combination evodiamine and anti-PD-1 treatment.ResultsWe showed that evodiamine significantly inhibited growth, induced apoptosis and cell cycle arrest at G2 phase of NSCLC cells. Evodiamine suppressed IFN-γ-induced PD-L1 expression in H1975 and H1650. MUC1-C mRNA and protein expression were decreased by evodiamine in NSCLC cells as well. Evodiamine could downregulate the PD-L1 expression and diminish the apoptosis of T cells. It inhibited MUC1-C expression and potentiated CD8+ T cell effector function. Meanwhile, evodiamine showed good anti-tumor activity in H1975 tumor xenograft, which reduced tumor size. Evodiamine exhibited anti-tumor activity by elevation of CD8+ T cells in vivo in Lewis lung carcinoma model. Combination evodiamine and anti-PD-1 mAb treatment enhanced tumor growth control and survival of mice.ConclusionsEvodiamine can suppress NSCLC by elevating of CD8+ T cells and downregulating of the MUC1-C/PD-L1 axis. Our findings uncover a novel mechanism of action of evodiamine and indicate that evodiamine represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat NSCLC cancer patients. MUC1-C overexpression is common in female, non-smoker, patients with advanced-stage adenocarcinoma.
| S-EPMC7677782 | biostudies-literature
Project description:ObjectiveTo assess the performance of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) radiomics features for predicting EGFR mutation status in patients with non-small cell lung cancer (NSCLC).Patients and methodsWe enrolled total 173 patients with histologically proven NSCLC who underwent preoperative 18F-FDG PET/CT. Tumor tissues of all patients were tested for EGFR mutation status. A PET/CT radiomics prediction model was established through multi-step feature selection. The predictive performances of radiomics model, clinical features and conventional PET-derived semi-quantitative parameters were compared using receiver operating curves (ROCs) analysis.ResultsFour CT and two PET radiomics features were finally selected to build the PET/CT radiomics model. Compared with area under the ROC curve (AUC) equal to 0.664, 0.683 and 0.662 for clinical features, maximum standardized uptake values (SUVmax) and total lesion glycolysis (TLG), the PET/CT radiomics model showed better performance to discriminate between EGFR positive and negative mutations with the AUC of 0.769 and the accuracy of 67.06% after 10-fold cross-validation. The combined model, based on the PET/CT radiomics and clinical feature (gender) further improved the AUC to 0.827 and the accuracy to 75.29%. Only one PET radiomics feature demonstrated significant but low predictive ability (AUC = 0.661) for differentiating 19 Del from 21 L858R mutation subtypes.ConclusionsEGFR mutations status in patients with NSCLC could be well predicted by the combined model based on 18F-FDG PET/CT radiomics and clinical feature, providing an alternative useful method for the selection of targeted therapy.
| S-EPMC7578399 | biostudies-literature