Different modes of stimuli delivery elicit changes in glutamate driven, experience-dependent interneuron response in C. elegans.

Memory-related neuronal responses are often elicited by sensory stimuli that recapitulate previous experience. Despite the importance of this sensory input processing, its underlying mechanisms remain poorly understood. Caenorhabditis elegans chemotax towards salt concentrations experienced in the presence of food. The amphid sensory neurons ASE-left and ASE-right respond to increases and decreases of ambient salt concentration in opposite manners. AIA, AIB and AIY interneurons are post-synaptic to the ASE pair and are thought to be involved in the processing of salt information transmitted from ASE. However, it remains elusive how the responses of these interneurons are regulated by stimulus patterns. Here we show that AIY interneurons display an experience-dependent response to gradual salt concentration changes but not to abrupt stepwise concentration changes. Animals with AIY intact (but AIA and AIB ablated) chemotax towards low salt concentrations similarly to wild-type animals after cultivation with low salt. ASE neurons transmit salt information about the environment through glutamatergic signaling, directing the activity of the interneurons AIY that promote movement towards favorable conditions.

Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery.

Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface-conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.

Enhancing Adoptive Cell Therapy of Cancer through Targeted Delivery of Small-Molecule Immunomodulators to Internalizing or Noninternalizing Receptors.

Adoptive cell therapy (ACT) has achieved striking efficacy in B-cell leukemias, but less success treating other cancers, in part due to the rapid loss of ACT T-cell effector function in vivo due to immunosuppression in solid tumors. Transforming growth factor-ß (TGF-ß) signaling is an important mechanism of immune suppression in the tumor microenvironment, but systemic inhibition of TGF-ß is toxic. Here we evaluated the potential of targeting a small molecule inhibitor of TGF-ß to ACT T-cells using PEGylated immunoliposomes. Liposomes were prepared that released TGF-ß inhibitor over ∼3 days in vitro. We compared the impact of targeting these drug-loaded vesicles to T-cells via an internalizing receptor (CD90) or noninternalizing receptor (CD45). When lymphocytes were preloaded with immunoliposomes in vitro prior to adoptive therapy, vesicles targeted to both CD45 and CD90 promoted enhanced T-cell expression of granzymes relative to free systemic drug administration, but only targeting to CD45 enhanced accumulation of granzyme-expressing T-cells in tumors, which correlated with the greatest enhancement of T-cell antitumor activity. By contrast, when administered i.v. to target T-cells in vivo, only targeting of a CD90 isoform expressed exclusively by the donor T-cells led to greater tumor regression over equivalent doses of free systemic drug. These results suggest that in vivo, targeting of receptors uniquely expressed by donor T-cells is of paramount importance for maximal efficacy. This immunoliposome strategy should be broadly applicable to target exogenous or endogenous T-cells and defines parameters to optimize delivery of supporting (or suppressive) drugs to these important immune effectors.