Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy

Abstract

Helper (CD4+) T cells perform direct therapeutic functions and augment responses of cells such as cytotoxic (CD8+) T cells against a wide variety of diseases and pathogens. Nevertheless, inefficient synthetic technologies for expansion of antigen-specific CD4+ T cells hinders consistency and scalability of CD4+ T cell-based therapies, and complicates mechanistic studies. Here we describe a nanoparticle platform for ex vivo CD4+ T cell culture that mimics antigen presenting cells (APC) through display of major histocompatibility class II (MHC II) molecules. When combined with soluble co-stimulation signals, MHC II artificial APCs (aAPCs) expand cognate murine CD4+ T cells, including rare endogenous subsets, to induce potent effector functions in vitro and in vivo. Moreover, MHC II aAPCs provide help signals that enhance antitumor function of aAPC-activated CD8+ T cells in a mouse tumor model. Lastly, human leukocyte antigen class II-based aAPCs expand rare subsets of functional, antigen-specific human CD4+ T cells. Overall, MHC II aAPCs provide a promising approach for harnessing targeted CD4+ T cell responses.

Genetically engineered CD80–pMHC-harboring extracellular vesicles for antigen-specific CD4+ T-cell engagement

“…However, MoDCs may be dysfunctional, for example, due to the presence of the tumor microenvironment ( Veglia and Gabrilovich, 2017 ). Moreover, several antigen-specific expansion approaches using artificial APCs (aAPCs) and cell-free systems have been described ( Ichikawa et al, 2020 ; Isser et al, 2022 ; Sun et al, 2022 ). The application of APCs or aAPCs introduces difficulties related to proliferation and the consumption of growth factors, while cell-free approaches require the laborious conjugation of pMHCs or costimulatory molecules.…”

“…The potency of T-cell stimulation relies on the high density of pMHC presentation, closely mimicking the role of the secondary lymphoid organs as the primary sites for naïve T-cell antigenic engagement ( González et al, 2005 ). To circumvent the drawbacks associated with the use of cells and create a high-density antigenic environment, various cell-free systems employing nano/micro-particles have been developed ( Singha et al, 2017 ; Rhodes et al, 2021 ; Isser et al, 2022 ).…”

Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

“…Due to this TiO 2 , there will be no loss in cell viability, and Jurkat T cells can produce higher cytokines in cancer immunotherapy . Schneck et al have shown the use of Jurkat T cells in adoptive T cell therapy by using iron-dextran nanoparticles coated with MHC II and costimulatory proteins to enhance CD8 + T cell cells activity, leading to an increased cytokine production and memory formation to kill cancer cells more efficiently . Many combined blockade therapy approaches are also being followed, such as PD-1/PD-L1 blockage or triple blockade of CTLA-4, PD-L1, and TIM3 receptors, in order to enhance the functions of T cells. , Researchers are also exploring combinations of CAR-T cell therapy with other treatments such as immune checkpoint inhibitors and targeted therapies.…”

Spiky Gold Nanoparticles, a Nanoscale Approach to Enhanced Ex Vivo T-Cell Activation

“…Scaling down the size of aAPCs to the nanoscale is a promising alternative approach since it provides an appropriate length scale for costimulation and higher ligand densities. Nanosized aAPCs including iron oxide, , lipid nanoparticles, and DNA origamis have shown successful expansion of T-cells. In the presence of nanoscale aAPCs, signaling molecules form a stable membrane domain with an average radius of 35–70 nm, and nanoparticles with ligand spacing similar to these domains result in enhanced T-cell activation .…”