Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed ...analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways.
Abstract Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and ...cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1 , Mafb , and Mrc1 , along with TSG-6 ligand Cd44 , predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors.
MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated.
We ...performed RNA and exome sequencing on an exploratory set of TRCC (n = 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n = 460).
Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of MITF, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3-TFE3 translocation.
This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes.
The purpose of this meta-analysis was to investigate the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex (PFC) of patients with Parkinson's ...disease (PD) and to determine the optimal rTMS parameters, such as the intensity, frequency and the delivered pattern of rTMS stimulation.
EMBASE, PubMed, Web of Science, MEDLINE, and Cochrane data bases were researched for papers published before March 12, 2018. Studies investigating the anti-depression effects of rTMS over PFC in patients with PD were considered. The main outcomes of pre- and post-rTMS treatment as well as score changes were all extracted. The mean effect size was estimated by calculating the standardized mean difference (SMD) with 95% confidence interval (CI) by using fixed or random effect models as appropriate.
Nine studies containing 137 PD patients with depression were included. The pooled results showed significant pre-post anti-depressive effects of rTMS over PFC in PD patients with depression (SMD = -0.80,
< 0.00001). The subgroup analyses of stimulation intensity, frequencies, and models also revealed significant effects (Intensities: 90% RMT: SMD = -1.16,
= 0.0006; >100% RMT: SMD = -0.82,
< 0.0001. Frequencies: < 1.0 Hz: SMD = -0.83,
= 0.03; 5.0 Hz: SMD = -1.10,
< 0.0001; ≥10.0 Hz: SMD = -0.55,
= 0.02. Models: Continuous: SMD = -0.79,
< 0.0001; Discontinuous: SMD = -0.84,
= 0.02). But the results of the studies with place-controlled designs were not significant (Overall: SMD = -0.27,
= 0.54. Intensities: 90% RMT: SMD = 0.27,
= 0.68; 100% RMT: SMD = -0.32,
= 0.33. Frequencies: 5.0 Hz: SMD = -0.87,
= 0.10; ≥10.0 Hz: SMD = 0.27,
= 0.66. Models: Continuous: SMD = -0.28,
= 0.68; Discontinuous: SMD = -0.32,
= 0.33). The greater effect sizes of rTMS with 90% RMT, 5.0 Hz in discontinuous days can be observed rather than the other parameters in both kinds of analyses across study design.
rTMS may have a significant positive pre-post anti-depressive effect over PFC on patients with depression, especially by using 5.0 Hz frequency with 90% RMT intensity in discontinuous days, which may produce better effects than other parameters. The real effect, though, was not different from that of the placebo. Future studies with larger sample sizes and high-quality studies are needed to further corroborate our results and to identify the optimal rTMS protocols.
Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, ...which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.
Display omitted
•Melanoma tumors with loss of IFN-γ signaling lack response to ipilimumab•Cell lines that are resistant to IFN-γ in vitro have defective IFN-γ pathway•Mice bearing IFNGR1 knockdown tumors have high mortality despite anti-CTLA-4 therapy
Genomic defects in the interferon pathway genes reduce the chance of response to immune checkpoint blockade therapy with anti-CTLA-4 for melanoma in humans and experimental models.
Enhancer of zeste homolog 2-mediated (EZH2-mediated) epigenetic regulation of T cell differentiation and Treg function has been described previously; however, the role of EZH2 in T cell-mediated ...antitumor immunity, especially in the context of immune checkpoint therapy, is not understood. Here, we showed that genetic depletion of EZH2 in Tregs (FoxP3creEZH2fl/fl mice) leads to robust antitumor immunity. In addition, pharmacological inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations of the Tregs and enhanced cytotoxic activity of Teffs. We observed that ipilimumab (anti-CTLA-4) increased EZH2 expression in peripheral T cells from treated patients. We hypothesized that inhibition of EZH2 expression in T cells would increase the effectiveness of anti-CTLA-4 therapy, which we tested in murine models. Collectively, our data demonstrated that modulating EZH2 expression in T cells can improve antitumor responses elicited by anti-CTLA-4 therapy, which provides a strong rationale for a combination trial of CPI-1205 plus ipilimumab.
•Discrete element method study on sand-tyre chips (STCh) with different tyre chip orientations is presented.•Rigorous calibration procedures for obtaining the microscopic parameters of STCh mixtures ...are presented.•The discrepancy in the reinforcement mechanism of different oriented tyre chips from a micromechanical viewpoint was studied.•It provides a theoretical reference for the design of scrap tyre chips in geotechnological application.
Sand-tyre chips (STCh) mixtures are emerging civil engineering materials that have been widely studied and applied. In the sand-tyre chips system, the mechanical behavior of sand matrix is improved attributed to the excellent property of tyres. However, the effect of tyre chip orientation for STCh mixtures is not fully appreciated, especially from the microscopic scale. In this paper, the microscopic behaviors of STCh mixtures with different orientation tyre chips were investigated employing the Discrete Element Method (DEM). The tyre chips model was constructed with sufficient consideration and the microscopic parameters of STCh model were confirmed by the calibration procedure. Simulation results illustrate that horizontal tyre chips more effectively enhance the mechanical properties of mixtures. The visualization of the specimen shows that the orientation of tyre chips can influence the evolution of system contact network, formation of shear band, and bulging deformation of specimen. The microscopic mechanism including the composition of strong contacts, coordination number, average normal contact force, sliding and rolling, energy storage and dissipation, and the tensile force in tyre chips were studied to evaluate the discrepancies of different orientation tyre chips. The mechanism of the reinforcement for tyre chips can receive further understanding from this study.
Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ICT in mUCC, ...we lack predictive biomarkers to guide patient selection. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Through multi-platform immuno-genomic analyses of baseline tumor tissues, we identified the mutation of AT-rich interactive domain-containing protein 1A (
) in tumor cells and expression of immune cytokine CXCL13 in the baseline tumor tissues as two predictors of clinical responses in a discovery cohort (
= 31). Further, reverse translational studies revealed that CXCL13
tumor-bearing mice were resistant to ICT, whereas
knockdown enhanced sensitivity to ICT in a murine model of bladder cancer. Next, we tested the clinical relevance of
mutation and baseline CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). We found that
mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data,
= 217; ARID1A data,
= 139, and IMvigor210, CXCL13 data,
= 348; ARID1A data,
= 275). We then interrogated CXCL13 expression plus
mutation as a combination biomarker in predicting response to ICT in CheckMate275 and IMvigor210. Combination of the two biomarkers in baseline tumor tissues suggested improved OS compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving ICT.
The purpose of this meta-analysis was to evaluate the therapeutic effect of transcranial direct current stimulation (tDCS) on mild to moderate Alzheimer disease (AD) patients.
PubMed, Embase, Web of ...Science, and Cochrane Library were searched until April 2018. The primary cognitive outcomes were extracted from included articles. A crude standardized mean difference with 95% CI was calculated by using fixed or random effect models.
Seven studies with 146 patients were included in this meta-analysis. The pooled result showed that tDCS significantly improved cognitive function of AD patients (standardized mean difference=0.37; 95% CI, 0.09-0.65; P=0.01). Subgroup analyses showed that: a single session of tDCS was significantly effective (P<0.05) whereas repeated sessions of tDCS was not lower current density (0.06 mA/cm) (P>0.05) but not higher current density (0.08 mA/cm) significantly improved cognitive performance; stimulating the temporal cortex (P<0.05) but not the left dorsal lateral prefrontal cortex significantly improved cognitive function of AD patients; and improved cognitive function occurred in the group with higher education (P<0.05) but not in the group with lower education.
Current evidence suggests that tDCS has a beneficial effect in mild to moderate AD patients. We must be cautious about the results of subgroup analysis given small sample sizes, and further well-designed studies with larger sample size are required to verify these results.
Introduction
Therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on motor recovery of Parkinson's disease (PD) have been reported; however, the protocols of these studies ...varied greatly. The aim of this meta‐analysis was to evaluate the optimal rTMS parameters for motor recovery of PD.
Methods
Electronic databases were searched for studies investigating the therapeutic effects of rTMS on motor function in patients with PD. The section III of the Unified Parkinson's Disease Rating Scale (UPDRS) was extracted as the primary outcome, and the standardized mean difference (SMD) with 95% confidence interval (CI) was calculated.
Results
Twenty‐three studies with a total of 646 participants were included. The pooled estimates of rTMS revealed significant short‐term (SMD, 0.37; p < 0.00001) and long‐term (SMD, 0.39; p = 0.005) effects on motor function improvement of PD. Subgroup analysis observed that high‐frequency rTMS (HF‐rTMS) was significant in improving motor function (SMD, 0.48; p < 0.00001), but low‐frequency rTMS (LF‐rTMS) was not. In particular, when HF‐rTMS targeted over the primary motor cortex (M1), in which the bilateral M1 revealed a larger effect size than unilateral M1. Compared to single‐session, multi‐session of HF‐rTMS over the M1 showed significant effect size. In addition, HF‐rTMS over the M1 with a total of 18,000–20,000 stimulation pulses yielded more significant effects (SMD, 0.97; p = 0.01) than other dosages.
Conclusions
In conclusion, multi‐session of HF‐rTMS over the M1 (especially bilateral M1) with a total of 18,000–20,000 pulses appears to be the optimal parameters for motor improvement of PD.
(a) rTMS improves motor recovery measured by UPDRS‐III scores in both the short‐ and long‐terms in people with PD. (b) HF‐rTMS was significantly more effective than LF‐rTMS in improving motor recovery measured by UPDRS‐III scores. (c) Multi‐session of HF‐rTMS stimulation over M1 (especially bilateral M1) with a total of 18,000–20,000 pulses appears to be the optimal parameters for achieving motor improvement in the short‐terms in people with PD.
PDF
