Integrin-Assisted T-Cell Activation on Nanostructured Hydrogels

Abstract

Adoptive cell therapy (ACT) has shown very promising results as treatment for cancer in a few clinical trials, such as the complete remissions of otherwise terminal leukemia patients. Nevertheless, the introduction of ACT into clinics requires overcoming not only medical but also technical challenges, such as the ex vivo expansion of large amounts of specific T-cells. Nanostructured surfaces represent a novel T-cell stimulation technique that enables us to fine-tune the density and orientation of activating molecules presented to the cells. In this work, we studied the influence of integrin-mediated cell-adhesion on T-cell activation, proliferation, and differentiation using nanostructured surfaces, which provide a well-defined system at the nanoscale compared with standard cultures. Specifically, we synthesized a polymeric polyethylene glycol (PEG) hydrogel cross-linked with two fibronectin-derived peptides, cyclic Arg-Gly-Asp (cRGD) and cyclic Leu-Asp-Val (cLDV), that are known to activate different integrins. Moreover, the hydrogels were decorated with a quasi-hexagonal array of gold nanoparticles (AuNPs) functionalized with the activating antibody CD3 to initiate T-cell activation. Both cLDV and cRGD hydrogels showed higher T-cell activation (CD69 expression and IL-2 secretion) than nonfunctionalized PEG hydrogels. However, only the cRGD hydrogels clearly supported proliferation giving a higher proportion of cells with memory (CD4CD45RO) than naı̈ve (CD4CD45RA) phenotypes when interparticle distances smaller than 150 nm were used. Thus, T-cell proliferation can be enhanced by the activation of integrins through the RGD sequence.

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

“…This enrichment plus expansion strategy resulted in more than 1000‐fold expansion of tumor‐specific lymphocytes from both mouse and human models in one week. Alternatively, considering the vital role of integrins in sustaining the interaction between the T‐cell receptor and MHC/antigen complex, Spatz group utilized fibronectin‐loaded PEG nanostructures to activate these integrins associated with T‐cell proliferation, thus increasing the T cell expansion rate …”

“…Alternatively, considering the vital role of integrins in sustaining the interaction between the T-cell receptor and MHC/antigen complex, Spatz group utilized fibronectin-loaded PEG nanostructures to activate these integrins associated with T-cell proliferation, thus increasing the T cell expansion rate. [211] Another limitation factor of ACT application is the immunosuppression in solid malignancies, where the effector functions of ACT T cells are subjected to immunosuppressive chemokines and abnormal tumor vasculature. Thus, ACT therapy is often combined with chemokine inhibitors.…”

A 3D Macroporous Alginate Graphene Scaffold with an Extremely Slow Release of a Loaded Cargo for In Situ Long‐Term Activation of Dendritic Cells

“…Although there are several studies on the injectable or implantable scaffolds for immunotherapy, there are a few aspects to be further improved, such as a limited stability in in vivo conditions, low drug loading capacity and short release time. The rGO‐based alginate scaffold showed several distinct properties.…”

“…Finally, the activated cells can migrate from scaffolds to secondary lymphoid organs and interact with other immune cells to provoke adaptive immune responses . Several 3D scaffolds such as alginate, polylactide‐ co ‐glycolide, mesoporous silica, and hydrogel have already been used to activate the immune system and inhibit tumor growth. Although these findings suggest that an implantable scaffold or an injectable hydrogel is a promising alternative for programing of host immune cells and for directing immune responses in vivo, long‐term activation of the immune system requires high loading and a slow and sustained release of the cargo from the carrier materials.…”

Emerging Nano‐/Microapproaches for Cancer Immunotherapy

“…Researchers formed a PEG hydrogel that cross‐linked with two fibronectin‐derived peptides, cyclic Arg‐Gly‐Asp (cRGD) and cyclic Leu‐Asp‐Val (cLDV), and further decorated it with a quasi‐hexagonal array of gold nanoparticles (AuNPs) functionalized with anti‐CD3. Both of the integrin binding ligands enhanced T‐cell activation, while only cRGD enhanced T‐cell proliferation with memory . Gold nanoparticles also induced higher siRNA transfection efficiency in cytotoxic T cells to which short laser pulses were applied …”