Lack of Functional Selectin Ligand Interactions Compromises Long Term Tumor Protection by CD8+ T Cells

Central memory CD8+ T cells expressing the adhesion molecule CD62L (L-selectin) are potent mediators of anti-cancer immunity due to their ability to proliferate extensively upon antigen re-stimulation. The interaction of selectin with its ligands mediates leukocyte rolling along high endothelial venules. Mice deficient in α(1,3) Fucosyltransferase IV and VII (FtDKO) lack functional L, P and E selectin ligands. Thus, we addressed whether the lack of selectin ligand interactions alters tumor protection by CD8+ T cells in FtDKO mice. Listeria monocytogenes-OVA (LM-OVA) infection evoked potent OVA-specific CD8+ T cells that proliferated and contracted at similar kinetics and phenotype in FtDKO and wild-type mice. Additionally, OVA-specific CD8+ T cells in both mouse strains exhibited similar phenotypic differentiation, in vivo cytolytic activity and IFN-γ expression. However, FtDKO mice succumbed to B16-OVA tumors significantly earlier than wild-type mice. In contrast, FtDKO mice evoked strong recall memory CD8+ T cell responses and protection to systemic LM-OVA re-challenge. The diminished tumor protection in FtDKO mice was not related to defective antigen presentation by dendritic cells or reduced proliferation of antigen-specific CD8+ T cells. However, WT or FtDKO OVA-specific CD8+ T cells showed significantly reduced ability to traffic to lymph nodes upon adoptive transfer into naïve FtDKO recipients. Furthermore, FtDKO OVA-specific CD8+ T cells displayed poor ability to infiltrate tumors growing in WT mice. These results reveal that selectin ligand expression on host endothelium as well CD8+ T cells may be important for their efficient and continued extravasation into peripheral tumors

Pyridyl disulfide reaction chemistry : an efficient strategy toward redox-responsive cyclic peptide–polymer conjugates

Cyclic peptide–polymer conjugates are capable of self-assembling into supramolecular polymeric nanotubes driven by the strong multiple hydrogen bonding interactions between the cyclic peptides. In this study, we have engineered responsive nanotubes by introducing a cleavable bond that responds to a reductant utilizing pyridyl disulfide reaction chemistry. Reactions between a cysteine containing cyclic peptide (CP-SH) and pyridyl disulfide containing polymers were initially studied, leading to the quantitative formation of cyclic peptide–polymer conjugates. An asymmetric cyclic peptide–polymer conjugate (PEG-CP-S-S-pPEGA) was then synthesized via orthogonal pyridyl disulfide reaction chemistry and NHS coupling chemistry. The disulfide linker formed by the pyridyl disulfide reaction chemistry was then selectively reduced to thiols in the presence of a reductant, enabling the transition of the conjugates from nonassembling unimers to self-assembled supramolecular polymeric nanotubes. It is anticipated that the pyridyl disulfide reaction chemistry will not only enrich the methodology toward the synthesis of cyclic peptide–polymer conjugates, but also lead to the construction of a new family of redox-responsive cyclic peptide–polymer conjugates and supramolecular polymeric nanotubes with tailored structures and functionalities

Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+ T Cell Responses

Vesicles comprised of the ether glycerolipids of the archaeon Methanobrevibacter smithii (archaeosomes) are potent adjuvants for evoking CD8+ T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+ T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189 and Gp10025-33 delivered in archaeosomes resulted in IFN-γ producing antigen-specific CD8+ T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+ T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines

Nanoscale arrays of antimony telluride single crystals by selective chemical vapor deposition

Arrays of individual single nanocrystals of Sb2Te3 have been formed using selective chemical vapor deposition (CVD) from a single source precursor. Crystals are self-assembled reproducibly in confined spaces of 100 nm diameter with pitch down to 500 nm. The distribution of crystallite sizes across the arrays is very narrow (standard deviation of 15%) and is affected by both the hole diameter and the array pitch. The preferred growth of the crystals in the orientation along the diagonal of the square holes strongly indicates that the diffusion of adatoms results in a near thermodynamic equilibrium growth mechanism of the nuclei. A clear relationship between electrical resistivity and selectivity is established across a range of metal selenides and tellurides, showing that conductive materials result in more selective growth and suggesting that electron donation is of critical importance for selective deposition

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc