Adoptive cell therapies using genetically engineered T cell receptor or chimeric antigen receptor T cells are emerging forms of immunotherapy that redirect T cells to specifically target cancer. ...However, tumor antigen heterogeneity remains a key challenge limiting their efficacy against solid cancers. Here, we engineered T cells to secrete the dendritic cell (DC) growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L-secreting T cells expanded intratumoral conventional type 1 DCs and substantially increased host DC and T cell activation when combined with immune agonists poly (I:C) and anti-4-1BB. Importantly, combination therapy led to enhanced inhibition of tumor growth and the induction of epitope spreading towards antigens beyond those recognized by adoptively transferred T cells in solid tumor models of T cell receptor and chimeric antigen receptor T cell therapy. Our data suggest that augmenting endogenous DCs is a promising strategy to overcome the clinical problem of antigen-negative tumor escape following adoptive cell therapy.
To investigate the characteristics of the laryngeal mucosal microvascular network in suspected laryngeal cancer patients, using narrow band imaging, and to evaluate the value of narrow band imaging ...endoscopy in the early diagnosis of laryngeal precancerous and cancerous lesions.
Eighty-five consecutive patients with suspected precancerous or cancerous laryngeal lesions were enrolled in the study. Endoscopic narrow band imaging findings were classified into five types (I to V) according to the features of the mucosal intraepithelial papillary capillary loops assessed.
A total of 104 lesions (45 malignancies and 59 nonmalignancies) was detected under white light and narrow band imaging modes. The sensitivity and specificity of narrow band imaging in detecting malignant lesions were 88.9 and 93.2 per cent, respectively. The intraepithelial papillary capillary loop classification, as determined by narrow band imaging, was closely associated with the laryngeal lesions' histological findings. Type I to IV lesions were considered nonmalignant and type V lesions malignant. For type Va lesions, the sensitivity and specificity of narrow band imaging in detecting severe dysplasia or carcinoma in situ were 100 and 79.5 per cent, respectively. In patients with type Vb and Vc lesions, the sensitivity and specificity of narrow band imaging in detecting invasive carcinoma were 83.8 and 100 per cent, respectively.
Narrow band imaging is a promising approach enabling in vivo differentiation of nonmalignant from malignant laryngeal lesions by evaluating the morphology of mucosal capillaries. These results suggest endoscopic narrow band imaging may be useful in the early detection of laryngeal cancer and precancerous lesions.
Quark clustering could occur in cold quark matter because of the strong coupling between quarks at realistic baryon densities of compact stars. Although one may still not be able to calculate this ...conjectured matter from the first principles, the intercluster interaction might be analogized to the interaction between inert molecules. Cold quark matter would then crystallize in a solid state if the intercluster potential is deep enough to trap the clusters in the wells. We apply the Lennard-Jones potential to describe the intercluster potential and derive the equations of state, which are stiffer than those derived in conventional models (e.g. MIT bag model). If quark stars are composed of the Lennard-Jones matter, they could have high maximum masses (>2 M⊙) as well as very low masses (<10−3 M⊙). These features could be tested by observations.
Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it ...is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.
Balling defect of the additively manufactured titanium lattice implants easily leads to muscle tissue rejection, which might cause failure of implantation. Electropolishing is widely used in surface ...polishing of complex components and has potential to deal with the balling defect. However, a clad layer could be formed on the surface of titanium alloy after electropolishing, which may affect the biocompatibility of the metal implants. To manufacture lattice structured β-type Ti-Ni-Ta-Zr (TNTZ) for bio-medical applications, it is necessary to investigate the impact of electropolishing on material biocompatibility. In this study, animal experiments were conducted to investigate the in vivo biocompatibility of the as-printed TNTZ alloy with or without electropolishing; and proteomics technology was used to elaborate the results. The following conclusions were drawn: (a) a 30% oxalic acid electropolishing treatment was effective in solving balling defects, and ~21 nm amorphous clad layer would be formed on the surface of the material after polishing; (b) the electropolished TNTZ suggested decreased cell cytotoxicity and improved blood biocompatibility as compared to as-printed TNTZ; (c) the amorphous clad layer could make a barrier to prevent Ta and Zr ions from penetrating into the muscle tissue, and could form a good tissue regeneration at the implantation site during 4 weeks, indicating that the electropolished TNTZ has the potential as implants; and (d) the cells attached to the electropolished TNTZ showed higher antioxidant capacity but less proliferation than attached to as-printed TNTZ.
Graphical Abstract
The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of ...metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
The effects of natural aging (NA) on subsequent artificial aging (AA) at 180°C in Al–Mg–Si–Cu alloys with varied Mg/Si ratios (0.5, 1 and 2) were systematically studied by Vickers micro-hardness ...measurements, differential scanning calorimetry and transmission electron microscopy (TEM). The alloy with large Mg/Si ratio possesses a significant negative NA effect on the maximum hardness achieved during AA preceded by an extended NA, while the alloy with small Mg/Si ratio shows a negligible negative NA effect. Though few lath-like Qʺ/L precipitates exist, needle-like βʺ precipitates are the primary hardening precipitates in all the peak-aged alloys. The negative NA effect is demonstrated to be determined by precipitate coarsening, which is manifested microscopically as the broader precipitate length distributions (PLD) and shift of PLD toward larger length range, in AA with the prolonging of NA. Our results suggest the nature of NA clusters is quite different in Al–Mg–Si–Cu alloy varying in Mg/Si ratio. Only a small fraction of NA clusters in alloy with large Mg/Si ratio are stable and could induce preferential growth of precipitates to be considerably coarsened during AA. A large fraction of stable NA clusters in alloy with low Mg/Si ratio lead to synchronous growth of βʺ precipitates, thus restricting the preferential growth.
In heavy-fermion compounds, the dual character of f electrons underlies their rich and often exotic properties like fragile heavy quasiparticles, a variety of magnetic orders and unconventional ...superconductivity. 5f-electron actinide materials provide a rich setting to elucidate the larger and outstanding issue of the competition between magnetic order and Kondo entanglement and, more generally, the interplay among different channels of interactions in correlated electron systems. Here, by using angle-resolved photoemission spectroscopy, we present the detailed electronic structure of USb2 and observe two different kinds of nearly flat bands in the antiferromagnetic state of USb2. Polarization-dependent measurements show that these electronic states are derived from 5f orbitals with different characters; in addition, further temperature-dependent measurements reveal that one of them is driven by the Kondo correlations between the 5f electrons and conduction electrons, while the other reflects the dominant role of the magnetic order. Our results on the low-energy electronic excitations of USb2 implicate orbital selectivity as an important new ingredient for the competition between Kondo correlations and magnetic order and, by extension, in the rich landscape of quantum phases for strongly correlated f electron systems.
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid ...parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
Response rates to immune checkpoint blockade (ICB; anti-PD-1/anti-CTLA-4) correlate with the extent of tumor immune infiltrate, but the mechanisms underlying the recruitment of T cells following ...therapy are poorly characterized. A greater understanding of these processes may see the development of therapeutic interventions that enhance T-cell recruitment and, consequently, improved patient outcomes. We therefore investigated the chemokines essential for immune cell recruitment and subsequent therapeutic efficacy of these immunotherapies.
The chemokines upregulated by dual PD-1/CTLA-4 blockade were assessed using NanoString-based analysis with results confirmed at the protein level by flow cytometry and cytometric bead array. Blocking/neutralizing antibodies confirmed the requirement for key chemokines/cytokines and immune effector cells. Results were confirmed in patients treated with immune checkpoint inhibitors using single-cell RNA-sequencing (RNA-seq) and paired survival analyses.
The CXCR3 ligands, CXCL9 and CXCL10, were significantly upregulated following dual PD-1/CTLA-4 blockade and both CD8
T-cell infiltration and therapeutic efficacy were CXCR3 dependent. In both murine models and patients undergoing immunotherapy, macrophages were the predominant source of CXCL9 and their depletion abrogated CD8
T-cell infiltration and the therapeutic efficacy of dual ICB. Single-cell RNA-seq analysis of patient tumor-infiltrating lymphocytes (TIL) revealed that CXCL9/10/11 was predominantly expressed by macrophages following ICB and we identified a distinct macrophage signature that was associated with positive responses to ICB.
These data underline the fundamental importance of macrophage-derived CXCR3 ligands for the therapeutic efficacy of ICB and highlight the potential of manipulating this axis to enhance patient responses.
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