RESUMO
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) shapes immunity by directing T cell function. Strategies to activate specific DC signaling pathways via targeted receptor engagement are crucial to unlocking type 1 cellular immunity. Here, we engineered a glycan-costumed virus-like particle (VLP) vaccine that delivers programmable peptide antigens to induce tumor-specific cellular immunity in vivo. VLPs encapsulating TLR7 agonists and decorated with a selective mannose-derived ligand for the lectin DC-SIGN induced robust DC activation and type 1 cellular immunity, whereas VLPs lacking this key DC-SIGN ligand failed to promote DC-mediated immunity. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, inhibiting tumor growth in a murine melanoma model. Thus, VLPs employing lectin-driven immune reprogramming provide a framework for advancing cancer immunotherapies.
RESUMO
Soluble human lectins are critical components of innate immunity. Genetic models suggest that lectins influence host-resident microbiota, but their specificity for commensal and mutualist species is understudied. Elucidating lectins' roles in regulating microbiota requires an understanding of which microbial species they bind within native communities. To profile human lectin recognition, we developed Lectin-Seq. We apply Lectin-Seq to human fecal microbiota using the soluble mannose-binding lectin (MBL) and intelectin-1 (hItln1). Although each lectin binds a substantial percentage of the samples (10 to 20%), the microbial interactomes of MBL and hItln1 differ markedly in composition and diversity. MBL binding is highly selective for a small subset of species commonly associated with humans. In contrast, hItln1's interaction profile encompasses a broad range of lower-abundance species. Our data uncover stark differences in the commensal recognition properties of human lectins.
Assuntos
Imunidade Inata , Lectinas , Humanos , Lectinas/genéticaRESUMO
Many common polymers, especially vinyl polymers, are inherently difficult to chemically recycle and are environmentally persistent. The introduction of low levels of cleavable comonomer additives into existing vinyl polymerization processes could facilitate the production of chemically deconstructable and recyclable variants with otherwise equivalent properties. Here, we report thionolactones that serve as cleavable comonomer additives for the chemical deconstruction and recycling of vinyl polymers prepared through free radical polymerization, using polystyrene (PS) as a model example. Deconstructable PS of different molar masses (â¼20-300 kDa) bearing varied amounts of statistically incorporated thioester backbone linkages (2.5-55 mol %) can be selectively depolymerized to yield well-defined thiol-terminated fragments (<10 kDa) that are suitable for oxidative repolymerization to generate recycled PS of nearly identical molar mass to the parent material, in good yields (80-95%). A theoretical model is provided to generalize this molar mass memory effect. Notably, the thermomechanical properties of deconstructable PS bearing 2.5 mol % of cleavable linkages and its recycled product are similar to those of virgin PS. The additives were also shown to be effective for deconstruction of a cross-linked styrenic copolymer and deconstruction and repolymerization of a polyacrylate, suggesting that cleavable comonomers may offer a general approach toward circularity of many vinyl (co)polymers.
Assuntos
Poliestirenos , Compostos de Vinila , Peso Molecular , Polimerização , Polímeros/química , Compostos de Vinila/químicaRESUMO
Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non-optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor-targeting aptamers for effective low-dose treatment. A nucleolin-recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC50 (31.9â nm) against MDA-MB-231 breast cancer cells inâ vitro, and exhibited inâ vivo efficacy at micro-dose injections (500 and 350â µg kg-1 dose-1 of DOX and CPT, respectively) that are 20-30-fold lower than their previously-reported MTDs. This approach represents a generalizable strategy for the safe and consistent delivery of combination drugs in oncology.