Current Advances in γδ T Cell-Based Tumor Immunotherapy

γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vd1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50-90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that aà T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-? and tumor necrosis factor-a and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer

Chloride-binding in organic–water mixtures: the powerful synergy of C–H donor groups within a bowl-shaped cavity

2,3,4,5-Tetrafluorobenzyl and imidazolium groups within an open-chain receptor allow for the effective binding of chloride in organic–water solution

Solid-Phase Synthesis of Gly-Ψ[CH(CF3)NH]-Peptides

The solid-phase synthesis of Gly-Ψ[CH(CF3)NH]-peptides is presented. In order to achieve this goal, the synthesis of Gly-Ψ[CH(CF3)NH]-dipeptides having the C-terminus unprotected, the N-terminus protected as Fmoc- or Teoc-, and possibly side chain functionalities protected with acid-labile protecting groups has been developed. A selected small library of six peptidomimetics, encompassing analogues of biological relevant peptides, have been obtained in high purity

Current Advances in γδ T Cell-Based Tumor Immunotherapy

γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50–90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αβ T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer

Anion-induced isomerization of fluorescent semi(thio)carbazones

In this work, we have investigated the properties of novel fluorescent semi(thio)carbazone systems with anions by UV-vis, spectrofluorimetric and NMR studies, in acetonitrile and DMSO solutions. Conformational preferences were determined by theoretical calculations within the DFT approach. For the free receptors, these studies pointed out a marked prevalence of anti conformations, which are stabilized by intramolecular H-bonds between the (thio)urea NH group and the imino nitrogen atom. For the julolidine-based thiosemicarbazone system, intermolecular interactions involving the thiourea NH groups and the S atoms of two receptor molecules were also found in the crystals, leading to the formation of supramolecular dimers. Theoretical studies showed that anion binding involved a change of the conformation of the receptors from anti to syn. In the syn isomers, two NH groups actually point in the same direction, thus favouring the binding of anions, e.g. the Y-shaped acetate ion. This thorough study on the novel semi(thio)carbazones provides useful information for the application of this type of molecule in all the fields of chemistry, in which urea-based systems are employed (e.g. anion recognition and transport, catalysis, soft materials, etc.)

Novel hydrogen- and halogen-bonding anion receptors based on 3-iodopyridinium units

Novel tripodal 3-iodopyridinium-based receptors were investigated through (i) UV-vis and NMR titrations with anions in solution, (ii) theoretical calculations, and (iii) X-ray diffraction studies. Their anion binding properties were compared to those of the monobranched model and/or non-halogenated model systems. Investigations in acetonitrile pointed out that the iodine atom in the meta position to pyridinium enhances anion affinity. According to computational studies, this effect seemed to depend on the electron-withdrawing nature of the iodine-substituents. Notably, 1 : 1 adducts were observed to form in solution with all the investigated anions. The strong de-shielding effect observed on the receptors' protons upon anion binding indicated their participation in hydrogen-bonds with the coordinated anion. This result was supported by theoretical calculations and, in the solid state, by X-ray diffraction studies on the complexes with nitrate and bromide. In the crystalline state, the pyridinium arms of the tripodal receptor assume a "2-up, 1-down" conformation. Both nitrate and bromide anions are included in the receptor's cavity, forming two hydrogen-bonding interactions with the protons of the "2-up" arms, and one halogen-bonding interaction with the C-I group of a second molecular cation. The combination of hydrogen and halogen bonds leads to supramolecular chains in the crystals