Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment

Dendritic cells (DCs) play a central role in the regulation of the balance between CD8 T cell immunity vs. tolerance to tumor antigens. Cross-priming, a process which DCs activate CD8 T cells by cross-presenting exogenous antigens, plays a critical role in generating anti-tumor CD8 T cell immunity. However, there are compelling evidences now that the tumor microenvironment (TME)-mediated suppression and modulation of tumor-infiltrated DCs (TIDCs) impair their function in initiating potent anti-tumor immunity and even promote tumor progression. Thus, DC-mediated cross-presentation of tumor antigens in tumor-bearing hosts often induces T cell tolerance instead of immunity. As tumor-induced immunosuppression remains one of the major hurdles for cancer immunotherapy, understanding how DCs regulate anti-tumor CD8 T cell immunity in particular within TME has been under intensive investigation. Recent reports on the Batf3-dependent type 1 conventional DCs (cDC1s) in anti-tumor immunity have greatly advanced our understanding on the interplay of DCs and CD8 T cells in the TME, highlighted by the critical role of CD103+ cDC1s in the cross-priming of tumor antigen-specific CD8 T cells. In this review, we will discuss recent advances in anti-tumor CD8 T cell cross-priming by CD103+ cDC1s in TME, and share perspective on future directions including therapeutic applications and memory CD8 T cell responses

Plasmacytoid Dendritic Cells and Cancer Immunotherapy

Despite largely disappointing clinical trials of dendritic cell (DC)-based vaccines, recent studies have shown that DC-mediated cross-priming plays a critical role in generating anti-tumor CD8 T cell immunity and regulating anti-tumor efficacy of immunotherapies. These new findings thus support further development and refinement of DC-based vaccines as mono-immunotherapy or combinational immunotherapies. One exciting development is recent clinical studies with naturally circulating DCs including plasmacytoid DCs (pDCs). pDC vaccines were particularly intriguing, as pDCs are generally presumed to play a negative role in regulating T cell responses in tumors. Similarly, DC-derived exosomes (DCexos) have been heralded as cell-free therapeutic cancer vaccines that are potentially superior to DC vaccines in overcoming tumor-mediated immunosuppression, although DCexo clinical trials have not led to expected clinical outcomes. Using a pDC-targeted vaccine model, we have recently reported that pDCs required type 1 conventional DCs (cDC1s) for optimal cross-priming by transferring antigens through pDC-derived exosomes (pDCexos), which also cross-prime CD8 T cells in a bystander cDC-dependent manner. Thus, pDCexos could combine the advantages of both cDC1s and pDCs as cancer vaccines to achieve better anti-tumor efficacy. In this review, we will focus on the pDC-based cancer vaccines and discuss potential clinical application of pDCexos in cancer immunotherapy

Dc-based vaccines for cancer immunotherapy

As the sentinels of the immune system, dendritic cells (DCs) play a critical role in initiating and regulating antigen-specific immune responses. Cross-priming, a process that DCs activate CD8 T cells by cross-presenting exogenous antigens onto their MHCI (Major Histocompatibility Complex class I), plays a critical role in mediating CD8 T cell immunity as well as tolerance. Current DC vaccines have remained largely unsuccessful despite their ability to potentiate both effector and memory CD8 T cell responses. There are two major hurdles for the success of DC-based vaccines: tumor-mediated immunosuppression and the functional limitation of the commonly used monocyte-derived dendritic cells (MoDCs). Due to their resistance to tumor-mediated suppression as inert vesicles, DC-derived exosomes (DCexos) have garnered much interest as cell-free therapeutic agents. However, current DCexo clinical trials have shown limited clinical benefits and failed to generate antigen-specific T cell responses. Another exciting development is the use of naturally circulating DCs instead of in vitro cultured DCs, as clinical trials with both human blood cDC2s (type 2 conventional DCs) and plasmacytoid DCs (pDCs) have shown promising results. pDC vaccines were particularly encouraging, especially in light of promising data from a recent clinical trial using a human pDC cell line, despite pDCs being considered tolerogenic and playing a suppressive role in tumors. However, how pDCs generate anti-tumor CD8 T cell immunity remains poorly understood, thus hindering their clinical advance. Using a pDC-targeted vaccine model, we have recently reported that while pDC-targeted vaccines led to strong cross-priming and durable CD8 T cell immunity, cross-presenting pDCs required cDCs to achieve cross-priming in vivo by transferring antigens to cDCs. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which similarly required cDCs for cross-priming of antigen-specific CD8 T cells. pDCexos thus represent a new addition in our arsenal of DC-based cancer vaccines that would potentially combine the advantage of pDCs and DCexos

DC-Derived Exosomes for Cancer Immunotherapy

As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy

A Novel Fluorogenic Coumarin Substrate for Monitoring Acid Phosphatase Activity at Low pH Environment

This article described the synthesis and application of 6-chloro-8-fluoro-4-methylumbelliferone phosphate (CF-MUP) in analyzing acid phosphatase activity. Compared to the existing MUP, the new coumarin phosphate, CF-MUP, demonstrateed much higher sensitivity and was more robust for detecting the activity of acid phosphatase than the classic substrate 4-methylumbelliferone phosphate (MUP). The product of enzyme reaction, 6-chloro-8-fluoro-4-methylumbelliferone (CF-MU) possesses strong fluorescence at ~450 nm with low pKa (4.7), high fluorescence quantum yield and pH independence in the physiological pH range. This new fluorescence dye, CF-MU, is a convenient tool for assays with buffer pH between 4.5 and 8

Long-lived magmatic evolution and mineralization resulted in formation of the giant Cuonadong Sn-W-Be polymetallic deposit, southern Tibet

The Cuonadong Sn-W-Be polymetallic deposit is the first Cenozoic leucogranite-related rare-metal deposit with giant metallogenic potential in the Himalayan orogen. However, controlling factors for the supernormal enrichment of beryllium, tin and tungsten in this deposit remain vague. In this study, we carried out systematic geochronological, whole-rock geochemical, and Sr-Nd isotopic analysis for the Cuonadong leucogranites, as well as detailed ore-forming geochronological analysis. The monazite U-Th-Pb, cassiterite U-Pb and muscovite Ar-Ar dating results, together with previously reported geochronological data, indicate that the major Cuonadong leucogranites (including, from old to young, weakly-oriented two-mica, two-mica granite and muscovite) were formed during ∼21-15 Ma, whereas the Sn-W-Be mineralization mainly occurred at ∼18-14 Ma. The Cuonadong leucogranites show strong peraluminous (A/CNK=1.09-1.22) features, and have high SiO2 (71.62-75.97 wt.%) and Al2O3 (14.04-16.09 wt.%) and low MgO (0.07-0.33 wt.%), MnO (0.01-0.15 wt.%) and total Fe2O3 (0.36-1.01 wt.%) contents, and are enriched in large ion lithophile elements (e.g., Rb, U, K, and Pb). These geochemical features together with enriched Sr-Nd isotopes (εNd(t) = -15.7 to -11.7; (87Sr/86Sr)i=0.71957-0.76313) indicate that the Cuonadong leucogranites belong to S-type granite and were derived from muscovite-induced dehydration melting of metapelites of the Higher Himalayan Crystalline Sequence. Perceptible linear variations of some major elements (e.g., Na2O, K2O, MnO, Fe2O3T, TiO2 and A/CNK) with increasing Rb/Sr ratios suggest these leucogranites experienced different degrees of evolution. Quantitative simulation calculations based on the whole-rock Rb, Sr, and Ba contents imply that the Cuonadong leucogranites experienced increasingly-strong fractional crystallization of plagioclase, K-feldspar and biotite from the weakly-oriented two-mica granite to two-mica granite and muscovite granite. Importantly, intense fractional crystallization leaded to notable enrichment of Sn, W and Be, although these elements are not obviously high in the relatively primitive magma for the Cuonadong leucogranites. Significantly, evident REE tetrad effects and deviation of twin-element pair ratios (K/Rb, K/Ba, Zr/Hf, Nb/Ta, and Y/Ho) from the chondritic values demonstrate that intense interaction between melts and F-rich aqueous fluids occurred during magmatic evolution. This implies that the Cuonadong leucogranites were derived from a volatile-rich magmatic system. The abundant volatiles probably remarkably facilitated and extended the fractional crystallization though lowering the solidus and viscosity of the magma. Thus, we propose that long-lived crystal fractionation (∼21-15 Ma) and mineralization (∼18-14 Ma) collectively leaded to supernormal enrichment of Sn, W, and Be in the Cuonadong Sn-W-Be polymetallic deposit. In contrast, the enrichment of Sn, W, and Be during the partial melting was insignificant.publishedVersio

Characterization and Discrimination of Prefabricated Grilled Fish with Different Packaging Methods Using Non-targeted Metabolomics

To explore the metabolites differences of grilled fish in different packages, liquid chromatography-tandem mass spectrometry was used to analyze and compare the metabolite profile of prefabricated grilled fish in tray packaging, vacuum packaging and modified atmosphere packaging through non-targeted metabolomics. The results showed that 318 metabolites were identified under secondary mass spectrometry information in the prefabricated grilled fish with different packaging. In this study, 47 differential metabolites were identified, including 10 fatty acids, 10 nucleotides, 9 amino acids, 7 organic acids and derivatives, 3 benzene and derivatives, 2 alcohol amines, and 6 unconfirmed metabolites, based on the variable importance projection value (VIP, VIP>1) and P<0.05 of the orthogonal partial least squares discriminant analysis model. Clustering heat map analysis of the relative content of 47 different metabolites was performed and the results showed differences in the relative content of metabolites in three types of packages. The relative contents of multiple flavor amino acids and adenosine monophosphate (AMP) were significantly higher in the modified atmosphere packaging than in the conventional vacuum package and tray package. The results revealed that modified atmosphere packaging effectively preserved the umami flavor of grilled fish, offering a basis for the development of novel and effective packaging for grilled fish

Influence of uniaxial tensile stress on the mechanical and piezoelectric properties of short-period ferroelectric superlattice

Tetragonal ferroelectric/ferroelectric BaTiO3/PbTiO3 superlattice under uniaxial tensile stress along the c axis is investigated from first principles. We show that the calculated ideal tensile strength is 6.85 GPa and that the superlattice under the loading of uniaxial tensile stress becomes soft along the nonpolar axes. We also find that the appropriately applied uniaxial tensile stress can significantly enhance the piezoelectricity for the superlattice, with piezoelectric coefficient d33 increasing from the ground state value by a factor of about 8, reaching 678.42 pC/N. The underlying mechanism for the enhancement of piezoelectricity is discussed

High circulating CD39+ regulatory T cells predict poor survival for sepsis patients

SummaryBackgroundSepsis encompasses two phases, the ‘hyper’-reactive phase and the ‘hypo’-reactive phase. The initial inflammatory stage is quickly counterbalanced by an anti-inflammatory response, which compromises the immune system, leading to immune suppression. Regulatory T cells (Tregs) have been implicated in the pathogenesis of sepsis by inducing immunosuppression; however, the role of CD39+ Tregs in the process of sepsis is uncertain. This study investigated the dynamic levels of CD39+ Tregs and their phenotypic change in sepsis.MethodsFourteen patients with systemic inflammatory response syndrome (SIRS), 42 patients with sepsis, and 14 healthy controls were enrolled. Sequential blood samples were used to analyze the numbers of CD39+ Tregs and their phenotypic changes. Survival at 28 days was used to evaluate the capacity of CD39+ Treg levels to predict mortality in sepsis patients.ResultsSepsis patients displayed a high percentage (3.13%, 1.46%, and 0.35%, respectively) and mean fluorescence intensity (MFI) (59.65, 29.7, and 24.3, respectively) of CD39+ Tregs compared with SIRS patients and healthy subjects. High-level expression of CD39+ Tregs was correlated with the severity of sepsis, which was reflected by the sepsis-related organ failure assessment score (r=0.322 and r=0.31, respectively). In addition, the expression of CD39+ Tregs was associated with survival of sepsis patients (p<0.01). By receiver-operating characteristic (ROC) curve analysis, the percentage and MFI of CD39+ Tregs showed similar sensitivities and specificities to predict mortality (74.2% and 85.1%, and 73.9% and 84.1%, respectively). Using Kaplan–Meier curves to assess the impact of CD39+ Tregs percentage and MFI on overall survival, we found that a high CD39+ Tregs percentage (p<0.001; >4.1%) and MFI (p<0.001; >49.2) were significantly associated with mortality. Phenotypically, CD39+ Tregs from sepsis patients showed high expression of CD38 and PD-1 (p<0.01 and p<0.01 respectively).ConclusionsIncreased expression of CD39+ Tregs was associated with a poor prognosis for sepsis patients, which suggests that CD39+ Treg levels could be used as a biomarker to predict the outcome of sepsis patients