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In tumors, a subset of CD8+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity.

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.

Background: The gut microbiome plays an important role in human health and disease. Gnotobiotic animal and in vitro cell-based models provide some informative insights into mechanistic crosstalk. However, there is no existing system for a long-term co-culture of a human colonic mucosal barrier with super oxygen-sensitive commensal microbes, hindering the study of human-microbe interactions in a controlled manner. Methods: Here, we investigated the effects of an abundant super oxygen-sensitive commensal anaerobe, Faecalibacterium prausnitzii, on a primary human mucosal barrier using a Gut-MIcrobiome (GuMI) physiome platform that we designed and fabricated. Findings: Long-term continuous co-culture of F. prausnitzii for two days with colon epithelia, enabled by continuous flow of completely anoxic apical media and aerobic basal media, resulted in a strictly anaerobic apical environment fostering growth of and butyrate production by F. prausnitzii, while maintaining a stable colon epithelial barrier. We identified elevated differentiation and hypoxia-responsive genes and pathways in the platform compared with conventional aerobic static culture of the colon epithelia, attributable to a combination of anaerobic environment and continuous medium replenishment. Furthermore, we demonstrated anti-inflammatory effects of F. prausnitzii through HDAC and the TLR-NFKB axis. Finally, we identified that butyrate largely contributes to the anti-inflammatory effects by downregulating TLR3 and TLR4. Conclusions: Our results are consistent with some clinical observations regarding F. prausnitzii, thus motivating further studies employing this platform with more complex engineered colon tissues for understanding the interaction between the human colonic mucosal barrier and microbiota, pathogens, or engineered bacteria.

Although the association between the microbiome and IBD and liver diseases is known, the cause and effect remain elusive. By connecting human microphysiological systems of the gut, liver, and circulating Treg and Th17 cells, we created a multi-organ model of ulcerative colitis (UC) ex vivo. The approach shows microbiome-derived short-chain fatty acids (SCFAs) to either improve or worsen UC severity, depending on the involvement of effector CD4 T cells. Using multiomics, we found SCFAs increased production of ketone bodies, glycolysis, and lipogenesis, while markedly reducing innate immune activation of the UC gut. However, during acute T cell-mediated inflammation, SCFAs exacerbated CD4+ T cell-effector function, partially through metabolic reprograming, leading to gut barrier disruption and hepatic injury. These paradoxical findings underscore the emerging utility of human physiomimetic technology in combination with systems immunology to study causality and the fundamental entanglement of immunity, metabolism, and tissue homeostasis.

Four new triphenyltin(IV) complexes containing [((E)-1-{2-hydroxy-5-[(E)-2-(aryl)-1-diazenyl]phenyl}methylidene)amino]acetate ligands (L) have been synthesized with formulations of Ph3SnLH. They have been studied by multinuclear (1H, 13C, 119Sn) NMR, 119Sn Mössbauer and IR spectroscopy. A full characterization of one complex, Ph3SnL1H (1), was accomplished by single crystal X-ray crystallography, which revealed the compound to be a macrocyclic tetramer. In the tetramer, the five coordinate tin atoms have distorted trigonal bipyramidal geometries with the three phenyl groups occupying equatorial positions, while an oxygen atom of the carboxylate group of one L ligand and the oxide O-atom (formerly the hydroxy group) of a second L ligand in an apical positions. The carboxylate ligands bridge adjacent tin atoms and coordinate in the zwitterionic form with the phenolic proton moved to the nearby nitrogen atom. 119Sn NMR results indicate that the tetrameric structures of the complexes in the solid state, in which the tin atoms are five-coordinated, dissociate in solution to yield four coordinate monomeric species

Five new organotin(IV) complexes of composition [Bz2SnL1]n (), [Bz3SnL1H⋅H2O] (), [Me2SnL2⋅H2O] (), [Me2SnL3] () and [Bz3SnL3H]n () (where L1 = (2S)-2-{[(E)-(4-hydroxypentan-2-ylidene)]amino}-4-methylpentanoate, L2 = (rac)-2-{[(E)-1-(2-hydroxyphenyl)methylidene]amino}-4-methylpentanoate and L3 = (2S)- or (rac)-2-{[(E)-1-(2-hydroxyphenyl)ethylidene]amino}-4-methylpentanoate) were synthesized and characterized using 1H NMR, 13C NMR, 119Sn NMR and infrared spectroscopic techniques. The crystal structure of reveals a distorted trigonal-bipyramidal geometry around the tin atom where the oxygen atoms of the carboxylate ligand and a water ligand occupy the axial positions, while the three benzyl ligands are located at the equatorial positions. On the other hand, the analogous derivative of enantiopure L3H () consists of polymeric chains, in which the ligand-bridged tin atoms adopt the same trans-Bz3SnO2 trigonal-bipyramidal configuration and are now coordinated to a phenolic oxygen atom instead of H2O. In , the OH hydrogen of the ketoimine substituent has moved to the nearby nitrogen atom while in the salicylidene derivative , the OH is located almost midway between the phenolic oxygen atom and the nitrogen atom of the C[DOUBLE BOND]N group. For the dibenzyltin derivative , a polymeric chain structure is observed as a result of a long intermolecular Sn⋅⋅⋅O bond involving the exocyclic carbonyl oxygen atom from the tridentate ligand of a neighbouring tin-complex unit. The tin atom in this complex has distorted octahedral coordination geometry. In contrast, the racemic dimethyltin(IV) complexes and display discrete monomeric structures with a distorted octahedral- and trigonal-bipyramidal geometry, respectively. The structures show that the coordination mode of the Schiff base ligand depends primarily on the number of bulky benzyl ligands (R) at the tin atom, as indeed found in the structures of related complexes where R = phenyl. With three bulky R groups, the tridentate ch

A series of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolin-8-olato}dimethyltin(IV), Me2Sn(L)2, and chloro-{5-[(E)-2-(aryl)-1-diazenyl]quinolin-8-olato}dimethyltin(IV), Me2SnCl(L), complexes have been synthesized by reacting the sodium salts of 5-[(E)-2-(aryl)-1-diazenyl)quinolin-8-ol (LH) and dimethyltin dichloride in 2:1 and 1:1 molar ratios, respectively. These complexes have been characterized by 1H, 13C, 119Sn NMR in solution and by IR and 119Sn Mössbauer spectroscopy in the solid state. The structures of two of the dimethyltin(IV) complexes, viz., Me2Sn(L2)2 (2) and Me2SnCl(L3). C7H8 (6) (L2 = 5-[(E)-2-(4′-methoxyphenyl)-1-diazenyl)quinolin-8-olate, L3 = 5-[(E)-2-(4′ ethoxyphenyl)- 1-diazenyl)quinolin-8-olate), were determined by single crystal X-ray diffraction. In general, the Me2Sn(L)2 complexes were found to adopt a distorted cis-octahedral arrangement, while Me2SnCl(L) complexes have a distorted trigonal bipyramidal coordination geometry around the tin atom in solution and in the solid state.

New trimethyltin(IV) derivatives with general formulae Me3Sn(HL), where HL is the monoanion of glycyltyrosine (H2L-1), glycylisoleucine (H2L-2), leucylleucine (H2L-3), leucyltyrosine (H2L-4), alanylvaline (H2L-5), and valylvaline (H2L-6) have been synthesized by the reaction of Me3SnCl and the sodium salt of the respective dipeptide with filtration of the NaCl formed. The bonding and coordination behaviour in the compounds synthesized are discussed on the basis of IR and 119Sn Mössbauer spectroscopic studies in the solid state and multinuclear 1H, 13C and 117Sn magnetic resonance in solution. These investigations suggest that, in the solid state, all the ligands in Me3Sn(HL) act as monoanionic bidentates coordinating through the COO− and NH2 groups. The 119Sn Mössbauer studies indicate that, for these polymeric derivatives, the polyhedron around tin in Me3Sn(HL) is a trigonal-bipyramid with the three methyl groups in the equatorial positions, while the axial positions are occupied by a carboxylic oxygen and the amino nitrogen atom from the adjacent molecule. The NMR data suggest that, in solution, an equilibrium between solvated and intramolecular coordinated monomeric species exists. The anti-inflammatory and cardiovascular activities and toxicity of all these compounds have been determined. All the compounds have also been screened against Staphylococcus aureus Mau (29/58), S. aureus Mau (78/71), Bacillus subtilis (18/64), Escherichia coli (326/71), E. coli, Candida albicans (Pn-10), Microsporum gypseum and Euglena gracillis. All the Me3Sn(IV) compounds exhibit good anti-inflammatory activity. Me3Sn(Gly[BOND]Tyr) and Me3Sn(Gly[BOND]Ile) display a potent cardiovascular activity and Me3Sn(Ala[BOND]Val) exhibits good antibacterial activity against all the strains chosen. Copyright © 2004 John Wiley & Sons, Ltd., FLWIN, info:eu-repo/semantics/published

New trimethyltin(IV) derivatives with general formulae Me3Sn(HL), where HL is the monoanion of glycyltyrosine (H2L-1), glycylisoleucine (H2L-2), leucylleucine (H2L-3), leucyltyrosine (H2L-4), alanylvaline (H2L-5), and valylvaline (H2L-6) have been synthesized by the reaction of Me3SnCl and the sodium salt of the respective dipeptide with filtration of the NaCl formed. The bonding and coordination behaviour in the compounds synthesized are discussed on the basis of IR and 119Sn Mössbauer spectroscopic studies in the solid state and multinuclear 1H, 13C and 117Sn magnetic resonance in solution. These investigations suggest that, in the solid state, all the ligands in Me3Sn(HL) act as monoanionic bidentates coordinating through the COO− and NH2 groups. The 119Sn Mössbauer studies indicate that, for these polymeric derivatives, the polyhedron around tin in Me3Sn(HL) is a trigonal-bipyramid with the three methyl groups in the equatorial positions, while the axial positions are occupied by a carboxylic oxygen and the amino nitrogen atom from the adjacent molecule. The NMR data suggest that, in solution, an equilibrium between solvated and intramolecular coordinated monomeric species exists. The anti-inflammatory and cardiovascular activities and toxicity of all these compounds have been determined. All the compounds have also been screened against Staphylococcus aureus Mau (29/58), S. aureus Mau (78/71), Bacillus subtilis (18/64), Escherichia coli (326/71), E. coli, Candida albicans (Pn-10), Microsporum gypseum and Euglena gracillis. All the Me3Sn(IV) compounds exhibit good anti-inflammatory activity. Me3Sn(Gly[BOND]Tyr) and Me3Sn(Gly[BOND]Ile) display a potent cardiovascular activity and Me3Sn(Ala[BOND]Val) exhibits good antibacterial activity against all the strains chosen. Copyright © 2004 John Wiley & Sons, Ltd., FLWIN, info:eu-repo/semantics/published

SCOPUS: er.j, FLWIN, info:eu-repo/semantics/published

SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

SCOPUS: ar.j, FLWIN, info:eu-repo/semantics/published

SCOPUS: er.j, FLWIN, info:eu-repo/semantics/published

Equimolar reactions of dibutyltin(IV) oxide with Schiff bases derived from amino-acids led to the formation of a new series of dibutyltin(IV) complexes of general formula, Bu2SnL [L=dianion of tridentate Schiff bases derived from the condensation of 2-hydroxy-1-naphthaldehyde or acetyl acetone with glycine (L-1), L-β-alanine (L-2), DL-valine (L-3), DL-4-aminobutyric acid (L-4), L-methionine (L-5), L-leucine (L-6) and phenylglycine (L-7)]. An attempt has been made to prove the structures of the resulting complexes on the basis of elemental analyses, conductance measurements and electronic, IR, multinuclear magnetic resonance (1H, 13C and 117Sn) and 119Sn Mössbauer spectral studies. The complexes have been tested against various bacteria [Streptococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus penicillin resistance (2500 units)] and fungi (Candida albicans, Cryptococcus neoformans, Sporotrichum schenckii,Trichophyton mentagrophytes and Aspergillus fumigatus). All the complexes showed moderate activity. The cytotoxicity of a few compounds has been screened in vitro against seven human tumour cell lines, viz. MCF-7, EVSA-T, WiDr, IGROV, M19 MEL, A498 and H226. The activities found experimentally were better than those obtained for cisplatin and carboplatin © 1997 John Wiley & Sons, Ltd., FLWIN, info:eu-repo/semantics/published

Four new triphenyltin(IV) complexes containing [((E)-1-{2-hydroxy-5-[(E)-2-(aryl)-1-diazenyl]phenyl}methylidene)amino]acetate ligands (L) have been synthesized with formulations of Ph3SnLH. They have been studied by multinuclear (1H, 13C, 119Sn) NMR, 119Sn Mössbauer and IR spectroscopy. A full characterization of one complex, Ph3SnL1H (1), was accomplished by single crystal X-ray crystallography, which revealed the compound to be a macrocyclic tetramer. In the tetramer, the five coordinate tin atoms have distorted trigonal bipyramidal geometries with the three phenyl groups occupying equatorial positions, while an oxygen atom of the carboxylate group of one L ligand and the oxide O-atom (formerly the hydroxy group) of a second L ligand in an apical positions. The carboxylate ligands bridge adjacent tin atoms and coordinate in the zwitterionic form with the phenolic proton moved to the nearby nitrogen atom. 119Sn NMR results indicate that the tetrameric structures of the complexes in the solid state, in which the tin atoms are five-coordinated, dissociate in solution to yield four coordinate monomeric species