Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses
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ABSTRACT:
SUBMITTER: Pedro Ventura
PROVIDER: S-SCDT-EMBOR-2022-55399V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1). Blockade of PD-1 signalling leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase Src homology 2 (SH2) domain–containing phosphatase (SHP)-2 is essential for the molecular cascade downstream PD-1, suggesting functional redundancy with the homologous phosphatase SHP-1. Therefore, we investigated the effect of concomitant SHP-1 and 2 deletion in T cells by knocking out these phosphatases under the CD4cre promoter. In vivo results not only indicate that Shp-1/2 deletion is insufficient to ameliorate tumour control, but also that it impairs the therapeutic effects of anti-PD1 treatment, affecting tumour-infiltrating CD8+ T cells. Notably, acute deletion of Shp-1/2 in effector T cells also fails to improve tumour control. In vitro results show that Shp-1/2-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analysis reveals substantial alterations in their proteome, including in apoptosis-related pathways. This data indicates that concomitant ablation of SHP-1/2 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.
2022-09-29 | PXD034897 | Pride
Project description:A frequent observation in several malignancies is the development of resistance to therapy that results in frequent tumor relapse and metastasis. Much of the tumor resistance phenotype comes from its heterogeneity that halts the ability of therapeutic agents to eliminate all cancer cells effectively. Tumor heterogeneity is, in part, controlled by cancer stem cells (CSC). CSC may be considered the reservoir of cancer cells as they exhibit properties of self-renewal and plasticity and the capability of reestablishing a heterogeneous tumor cell population. The endowed resistance mechanisms of CSC are mainly attributed to several factors including cellular quiescence, accumulation of ABC transporters, disruption of apoptosis, epigenetic reprogramming, and metabolism. There is a current need to develop new therapeutic drugs capable of targeting CSC to overcome tumor resistance. Emerging in vitro and in vivo studies strongly support the potential benefits of combination therapies capable of targeting cancer stem cell-targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This review will address the main characteristics, therapeutic implications, and perspectives of targeting CSC to improve current anticancer therapeutics.
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Project description:Many real-world searches (e.g., radiology and baggage screening) have rare targets. When targets are rare, observers perform rapid, incomplete searches, leading to higher miss rates. To improve search for rare (10% prevalence) targets, we provided eye movement feedback (EMF) to observers during their searches. Although the nature of the EMF varied across experiments, each method informed observers about the regions of the display that had not yet been inspected. We hypothesized that feedback would help guide attention to unsearched areas and increase the proportion of the display searched before making a target-absent response, thereby increasing accuracy. An eye tracker was used to mark fixated areas by either removing a semiopaque gray overlay (Experiments 1 and 4) as portions of the display were fixated or by adding the overlay once the eye left a segment of the image (Experiments 2 and 4). Experiment 3 provided automated EMF, such that a new region was uncovered every 540 milliseconds. Across experiments, we varied whether people searched for "Waldo" in images from "Where's Waldo?" search books or searched for a T among offset Ls. We found weak evidence that EMF improves accuracy in Experiment 1. However, in the remaining experiments, EMF had no effect (Experiment 4), or even reduced accuracy (Experiments 2 and 3). We conclude that the one positive result we found is likely a Type I error and that the EMF method that we used is unlikely to improve visual search performance.
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Project description:T cells play a central role in the immune response to many of the world's major infectious diseases. In this study we investigated the tumour necrosis factor receptor superfamily costimulatory molecule, 4-1BBL (CD137L, TNFSF9), for its ability to increase T cell immunogenicity induced by a variety of recombinant vectored vaccines. To efficiently test this hypothesis, we assessed a number of promoters and developed a stable bi-cistronic vector expressing both the antigen and adjuvant. Co-expression of 4-1BBL, together with our model antigen TIP, was shown to increase the frequency of murine antigen-specific IFN-? secreting CD8(+) T cells in three vector platforms examined. Enhancement of the response was not limited by co-expression with the antigen, as an increase in CD8(+) immunogenicity was also observed by co-administration of two vectors each expressing only the antigen or adjuvant. However, when this regimen was tested in non-human primates using a clinical malaria vaccine candidate, no adjuvant effect of 4-1BBL was observed limiting its potential use as a single adjuvant for translation into a clinical vaccine.
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Project description:BackgroundAcute respiratory distress syndrome (ARDS) is associated with high mortality rates. ARDS patients suffer from severe hypoxemia, and extracorporeal membrane oxygenation (ECMO) therapy may be necessary to ensure oxygenation. ARDS has various etiologies, including trauma, ischemia-reperfusion injury or infections of various origins, and the associated immunological responses may vary. To support the immunological response in this patient collective, we used intravenous IgM immunoglobulin therapy to enhance the likelihood of pulmonary recovery.MethodsARDS patients admitted to the intensive care unit (ICU) who were placed on ECMO and treated with (IVIG group; n = 29) or without (control group; n = 28) intravenous IgM-enriched immunoglobulins for 3 days in the initial stages of ARDS were analyzed retrospectively.ResultsThe baseline characteristics did not differ between the groups, although the IVIG group showed a significantly reduced oxygenation index compared to the control group. We found no differences in the length of ICU stay or ventilation parameters. We did not find a significant difference between the groups for the extent of inflammation or for overall survival.ConclusionWe conclude that administration of IgM-enriched immunoglobulins as an additional therapy did not have a beneficial effect in patients with severe ARDS requiring ECMO support.Trial registrationClinical Trials: NCT02961166; retrospectively registered.
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Project description:Purpose:Anticancer drug delivery systems are often limited by hurdles, such as off-target distribution, slow cellular internalization, limited lysosomal escape, and drug resistance. To overcome these limitations, we have developed a stable nitric oxide (NO)-releasing nanoparticle (polystyrene-maleic acid [SMA]-tert-dodecane S-nitrosothiol [tDodSNO]) with the aim of enhancing the anticancer properties of doxorubicin (Dox) and a Dox-loaded nanoparticle (SMA-Dox) carrier. Materials and methods:Effects of SMA-tDodSNO and/or in combination with Dox or SMA-Dox on cell viability, apoptosis, mitochondrial membrane potential, lysosomal membrane permeability, tumor tissue, and tumor growth were studied using in vitro and in vivo model of triple-negative breast cancer (TNBC). In addition, the concentrations of SMA-Dox and Dox in combination with SMA-tDodSNO were measured in cells and tumor tissues. Results:Combination of SMA-tDodSNO and Dox synergistically decreased cell viability and induced apoptosis in 4T1 (TNBC cells). Incubation of 4T1 cells with SMA-tDodSNO (40 µM) significantly enhanced the cellular uptake of SMA-Dox and increased Dox concentration in the cells resulting in a twofold increase (P<0.001). Lysosomal membrane integrity, evaluated by acridine orange (AO) staining, was impaired by 40 µM SMA-tDodSNO (P<0.05 vs control) and when combined with SMA-Dox, this effect was significantly potentiated (P<0.001 vs SMA-Dox). Subcutaneous administration of SMA-tDodSNO (1 mg/kg) to xenografted mice bearing 4T1 cells showed that SMA-tDodSNO alone caused a twofold decrease in the tumor size compared to the control group. SMA-tDodSNO in combination with SMA-Dox resulted in a statistically significant 4.7-fold reduction in the tumor volume (P<0.001 vs control), without causing significant toxicity as monitored through body weight loss. Conclusion:Taken together, these results suggest that SMA-tDodSNO can be used as a successful strategy to increase the efficacy of Dox and SMA-Dox in a model of TNBC.
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Project description:We investigated if a carbohydrate (CHO) mouth rinse may attenuate global fatigue and improve 4-km cycling time trial (TT4km) performance. After a preliminary session, cyclists (n = 9) performed a TT4km after a CHO or placebo (PLA) mouth rinse. Mean power output, time, and ratings of perceived exertion (RPE) were recorded throughout the TT4km. Twitch interpolation responses (%VA; voluntary activation and ?Tw; delta peak twitch torque) were compared pre and post TT4km with traditional statistics and effect size (ES) analysis. Time-to-complete the 4 km and mean power output were comparable between CHO (386.4 ± 28.0 s) and PLA (385.4 ± 22.4 s). A lower central (p = 0.054) and peripheral (p = 0.02) fatigue in CHO than in PLA were suggested by an extremely-large ES in %VA (manipulation main effect: p = 0.052, d = 1.18; manipulation-by-time interaction effect: p = 0.08, d = 1.00) and an extremely, very-large ES in ?Tw (manipulation main effect: p = 0.07, d = 0.97; time-by-manipulation interaction effect: p = 0.09, d = 0.89). The RPE increased slower in CHO than in PLA (p = 0.051; d = 0.7). The apparent reduction in global fatigue (central and peripheral) and RPESLOPE with only one CHO mouth rinse were not translated into improved TT4km performance. Further tests may be required to verify if these likely differences in global fatigue might represent an edge in the short-lasting cycling time trial performance.
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Project description:Background. Propensity score usage seems to be growing in popularity leading researchers to question the possible role of propensity scores in prediction modeling, despite the lack of a theoretical rationale. It is suspected that such requests are due to the lack of differentiation regarding the goals of predictive modeling versus causal inference modeling. Therefore, the purpose of this study is to formally examine the effect of propensity scores on predictive performance. Our hypothesis is that a multivariable regression model that adjusts for all covariates will perform as well as or better than those models utilizing propensity scores with respect to model discrimination and calibration. Methods. The most commonly encountered statistical scenarios for medical prediction (logistic and proportional hazards regression) were used to investigate this research question. Random cross-validation was performed 500 times to correct for optimism. The multivariable regression models adjusting for all covariates were compared with models that included adjustment for or weighting with the propensity scores. The methods were compared based on three predictive performance measures: (1) concordance indices; (2) Brier scores; and (3) calibration curves. Results. Multivariable models adjusting for all covariates had the highest average concordance index, the lowest average Brier score, and the best calibration. Propensity score adjustment and inverse probability weighting models without adjustment for all covariates performed worse than full models and failed to improve predictive performance with full covariate adjustment. Conclusion. Propensity score techniques did not improve prediction performance measures beyond multivariable adjustment. Propensity scores are not recommended if the analytical goal is pure prediction modeling.
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Project description:Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell-mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.
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