The role of exhausted natural killer cells in the immunopathogenesis and treatment of leukemia.

The immune responses to cancer cells involve both innate and acquired immune cells. In the meantime, the most attention has been drawn to the adaptive immune cells, especially T cells, while, it is now well known that the innate immune cells, especially natural killer (NK) cells, play a vital role in defending against malignancies. While the immune cells are trying to eliminate malignant cells, cancer cells try to prevent the function of these cells and suppress immune responses. The suppression of NK cells in various cancers can lead to the induction of an exhausted phenotype in NK cells, which will impair their function. Recent studies have shown that the occurrence of this phenotype in various types of leukemic malignancies can affect the prognosis of the disease, and targeting these cells may be considered a new immunotherapy method in the treatment of leukemia. Therefore, a detailed study of exhausted NK cells in leukemic diseases can help both to understand the mechanisms of leukemia progression and to design new treatment methods by creating a deeper understanding of these cells. Here, we will comprehensively review the immunobiology of exhausted NK cells and their role in various leukemic malignancies. Video Abstract.

Targeting the CTLA-4/B7 axes in glioblastoma: preclinical evidence and clinical interventions.

INTRODUCTION: Glioblastoma Multiforme (GBM) is one of the fatal cancers of the Central Nervous System (CNS). A variety of reasons exist for why previous immunotherapy strategies, especially Immune Checkpoint Blockers (ICBs), did not work in treating GBM patients. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint receptor. Its overexpression in cancer and immune cells causes tumor cell progression. CTLA-4 suppresses anti-tumor responses inside the GBM tumor-immune microenvironment. AREAS COVERED: It has been attempted to explain the immunobiology of CTLA-4 as well as its interaction with different immune cells and cancer cells that lead to GBM progression. Additionally, CTLA-4 targeting studies have been reviewed and CTLA-4 combination therapy, as a promising therapeutic target and strategy for GBM immunotherapy, is recommended. EXPERT OPINION: CTLA-4 could be a possible supplement for future cancer immunotherapies of GBM. However, many challenges remain such as the high toxicity of CTLA-4 blockers, and the unresponsiveness of most patients to immunotherapy. For the future clinical success of CTLA-4 blocker therapy, combination approaches with other targeted treatments would be a potentially effective strategy. Going forward, predictive biomarkers can be used to reduce trial timelines and increase the chance of success.

Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model.

PURPOSE: Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS: We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS: Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION: These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.

Combination Cancer Immunotherapy with Dendritic Cell Vaccine and Nanoparticles Loaded with Interleukin-15 and Anti-beta-catenin siRNA Significantly Inhibits Cancer Growth and Induces Anti-Tumor Immune Response.

PURPOSE: The invention and application of new immunotherapeutic methods can compensate for the inefficiency of conventional cancer treatment approaches, partly due to the inhibitory microenvironment of the tumor. In this study, we tried to inhibit the growth of cancer cells and induce anti-tumor immune responses by silencing the expression of the ß-catenin in the tumor microenvironment and transmitting interleukin (IL)-15 cytokine to provide optimal conditions for the dendritic cell (DC) vaccine. METHODS: For this purpose, we used folic acid (FA)-conjugated SPION-carboxymethyl dextran (CMD) chitosan (C) nanoparticles (NPs) to deliver anti-ß-catenin siRNA and IL-15 to cancer cells. RESULTS: The results showed that the codelivery of ß-catenin siRNA and IL-15 significantly reduced the growth of cancer cells and increased the immune response. The treatment also considerably stimulated the performance of the DC vaccine in triggering anti-tumor immunity, which inhibited tumor development and increased survival in mice in two different cancer models. CONCLUSIONS: These findings suggest that the use of new nanocarriers such as SPION-C-CMD-FA could be an effective way to use as a novel combination therapy consisting of ß-catenin siRNA, IL-15, and DC vaccine to treat cancer.

Simultaneous silencing of the A2aR and PD-1 immune checkpoints by siRNA-loaded nanoparticles enhances the immunotherapeutic potential of dendritic cell vaccine in tumor experimental models.

Following various immunotherapies, lack of proper anti-tumor immune responses is considered a significant problem in novel cancer therapeutic approaches. The expression of inhibitory checkpoint molecules on tumor-infiltrating T cells is one of the main reasons for the ineffectiveness of various immunotherapies. Therefore, we decided to inhibit two of the most important immune checkpoints expressed on tumor-associated T cells, PD-1 and A2aR. Ligation of PD-1 with PD-L1 and A2aR with adenosine significantly suppress T cell responses against tumor cells. Whitin tumors, specific inhibition of these molecules on T cells is of particular importance for successful immunotherapy as well as the elimination of treatment-associated side-effects. Thus, in this study, superparamagnetic iron oxide (SPION) nanoparticles (NPs) were covered by chitosan lactate (CL), functionalized with TAT peptide, and loaded with siRNA molecules against PD-1 and A2aR. Appropriate physicochemical properties of the prepared NPs resulted in efficient delivery of siRNA to tumor-derived T cells and suppressed the expression of A2aR and PD-1, ex vivo. T cell functions such as cytokine secretion and proliferation were considerably enhanced by the downregulation of these molecules which led to an increase in their survival time. Interestingly, treatment of CT26 and 4T1 mouse tumors with siRNA-loaded NPs not only inhibited tumor growth but also markedly increased anti-tumor immune responses and survival time. The results strongly support the efficacy of SPION-CL-TAT NPs loaded with anti-PD-1/A2aR siRNAs in cancer therapy and their further development for cancer patients in the near future.

Fabrication of nanofibers using sodium alginate and Poly(Vinyl alcohol) for the removal of Cd2+ ions from aqueous solutions: adsorption mechanism, kinetics and thermodynamics.

Nowadays, separation of heavy metals from polluted wastewater is one of the most important environmental issues, and various methods have been investigated for treating polluted water and industrial wastewater. Surface adsorption using an inexpensive, biodegradable and environmentally consistent adsorbent can be considered an efficient and cost-effective method. One of these adsorbents is sodium alginate (SA). The purpose of this study was to fabricate composite nanofibers using poly (vinyl alcohol) (PVA) and sodium alginate to remove cadmium metal ion from aqueous solutions. For this purpose, polymer solutions consisting of poly (vinyl alcohol) (10% wt)/sodium alginate (2% wt) with three volume ratios of 0/100, 20/80 and 40/60 were first made, and then nanofibers were produced from the resulting solutions by electro-spinning process. The prepared nanofibers were examined by scanning electron microscopy (SEM) and the synthetic poly (vinyl alcohol)/sodium alginate nanofibers at a ratio of 40/60 were selected as adsorbent. The obtained nanofibers were characterized by Fourier-transform infrared spectroscopy (FTIR). The synthesized adsorbent was used to remove the aqueous solution of cadmium metal; the effect of various parameters such as changes in initial metal ion concentration, pH, temperature, contact time and stirring speed on the adsorption process were investigated, and optimum values of the parameters were obtained. The maximum amount of equilibrium adsorption under optimum experimental conditions was 67.05 mg/gr. The Taguchi experiment design method was used to optimize the three effective factors in the cadmium ion adsorption process. The results of the adsorption process were adapted to different adsorption isotherms such as Langmuir and Freundlich isotherms. The fit of the laboratory data to the Langmuir model was better, and the maximum adsorption capacity through this model was obtained equal to 93.163 mg/g of the adsorbent. Since the performance of an adsorbent depends on the duration of the adsorption process, the kinetics of the adsorption process were investigated by pseudo-first-order equation and pseudo-second-order equation. Moreover, the results indicated that the laboratory data showed a better fit to the pseudo-second-order model. Finally, the thermodynamic perspective was examined, and the process was found to be endothermic and spontaneous. The results showed the optimum values for maximum cadmium uptake.

Predictive Materials Design of Magnetic Random-Access Memory Based on Nanoscale Atomic Structure and Element Distribution.

Magnetic tunnel junctions (MTJs) capable of electrical read and write operations have emerged as a canonical building block for nonvolatile memory and logic. However, the cause of the widespread device properties found experimentally in various MTJ stacks, including tunneling magnetoresistance (TMR), perpendicular magnetic anisotropy (PMA), and voltage-controlled magnetic anisotropy (VCMA), remains elusive. Here, using high-resolution transmission electron microscopy and energy-dispersive X-ray spectroscopy, we found that the MTJ crystallization quality, boron diffusion out of the CoFeB fixed layer, and minimal oxidation of the fixed layer correlate with the TMR. As with the CoFeB free layer, seed layer diffusion into the free layer/MgO interface is negatively correlated with the interfacial PMA, whereas the metal-oxides concentrations in the free layer correlate with the VCMA. Combined with formation enthalpy and thermal diffusion analysis that can explain the evolution of element distribution from MTJ stack designs and annealing temperatures, we further established a predictive materials design framework to guide the complex design space explorations for high-performance MTJs. On the basis of this framework, we demonstrate experimentally high PMA and VCMA values of 1.74 mJ/m2 and 115 fJ/V·m-1 with annealing stability above 400 °C.

Adsorptive removal of Pb (II) by means of hydroxyapatite/chitosan nanocomposite hybrid nanoadsorbent: ANFIS modeling and experimental study.

In the current study, the prediction efficiency of lead adsorption by highly functional nanocomposite adsorbent of hydroxyapatite (HAp)/chitosan using ANFIS system was investigated. In this regard, the nanocomposite was applied in order to investigate the lead adsorption capacity. The operational conditions were pH (2-6), contact time between lead ions and adsorbent (15-360 min), shaker velocity (80-400 rpm), temperature (25-55 °C), amount of adsorbent (0.01-1.5 g), lead initial concentration (0-5000 ppm) and HAp concentration (10-75%). The effect of each parameter was investigated, and then the ANFIS was employed to model the adsorption process using the obtained experimental results. The ANFIS modeled the results with total average error and total average of absolute error less than 0.0646% and 4.2428%, respectively, for training data. Moreover, the coefficient of determination for training data and testing data were found to be 0.9999 and 0.9823, respectively. In addition, granular chitosan and HAp nanoparticles adsorption capabilities were compared with nanocomposite of HAp (20%wt)/chitosan adsorbent. It was found that nanocomposite adsorbent had a higher adsorption capability than other adsorbents.