3.1 Engineered DC is the latest treatment strategy for NSCLC
Artificial APCs (aAPCs), which can be readily prepared from “off-the-shelf” components, are promising alternatives to custom-made autologous APCs that can effectively stimulate antigen-specific T cells in vitro [105-106]. Several aAPCs for in vitro activation and expansion of antigen-specific T cells have been successfully developed [107]. For example, cell-based aAPCs have been studied in several different cell lines, including fly black stomach cells [108], NIH3T3 mouse fibroblasts [109], and K562 human erythroid leukemia cells [110]. These cells were generated using retroviral or lentiviral transduction to introduce molecules that provide TCR, costimulatory, and adhesion molecules necessary for synaptic formation. Given that these cells can be stored for a long time, they can be easily obtained from source companies and distributors[111]. Although cellular aAPCs can induce a high expansion rate of CD8+ T cells, their performance of specific control on the expression level of T cell activation signals is limited. In addition, non-tumor antigens and other stimulatory or inhibitory molecules may be present in cellular aAPCs.
The cell-free aAPCs have been developed to better define the transmission of different signals and avoid the use of allogeneic cells[112]. Compared to cellular aAPCs, acellular aAPCs allow for more stringent control over the signals delivered and are attractive tools because of their relatively easy preparation through micro latex, polyethylene glycol, magnetic beads, and lipid-based vesicles [113]. In general, the aAPCs approach has focussed on the induction of CD8+ CTLs through MHC I stimulation because these cells are capable of antigen-specific tumor cell lysis [114-115]. Other immune cells, such as CD4+ T helper cells, mediate anticancer immune responses by activating CTLs. Artificial APCs comprising various sizes, shapes, surface ligand distribution, and ligand mobility have been developed, and these properties affect the level of T cell activation. Various cell-free aAPCs structures reflect different attempts to simulate different aspects of natural DC [112].
It has been shown that DCs usually exhibit poor maturity in the tumor microenvironment and are less effective in presenting tumor antigens[116]. Therefore, targeting delivery of antigens and adjuvants to cells in vivo is an important method for developing DC vaccines. Sun et al developed intelligent artificial DC cells (iDCs) comprising nanoparticles loaded with a photothermal agent (IR-797) and coated with mature DC cell membranes. The DC cell membrane on the surface of iDCs preserves the ability to present antigens and prime T cells. The iDCs injected into mice enter lymph nodes and stimulate T cell activation and proliferation. Cancer-specific T cells are activated in a TCR-dependent manner and kill tumor cells upon TCR binding of antigens presented via MHCs. Alternately, activated T cells secrete cytokines (TNF- α),reducing the expression of heat shock proteins (HSPs) in tumor cells, thus, enhancing the sensitivity of tumor cells to heat stress. Subsequently, mild photothermal treatment can kill the remaining tumor cells (42-45°C). At the same time, low temperature photoheat can also induce the death of immunogenic cells, thereby activating the body’s own DC cells and restarting the tumor immune cycle. As a new precise antitumor nanosystem, iDCs combine the advantages of DC cell immunotherapy and photothermal therapy. Consequently, iDCs effectively enhance the antitumor immune response of the body, improve the efficacy of tumor treatment, and provide a new strategy for immunosensitized low-temperature photothermal therapy[117]. Concurrently, Suarez et al developed an Artificial Immune Modulation nanoparticle (AIM-np) technology, a customizable “off-the-shelf” technology that can be used for synthesizing APCs to guide antigen-specific natural CD8+ T cells. AIM-np provides a controlled method for antigen presentation and T cell costimulation by directly binding to antigen-specific T cells. This method uses proprietary nanoparticles combined with a proprietary manufacturing process to enrich and expand antigen-specific CD8+ T-cell products with consistent purity, identity, and composition required for effective and durable anti-tumor response. AIM-np consists of superparamagnetic iron oxide nanoparticles as the main structure, which is decorated with two humanized signal proteins. HLA-A2-IgG4 hinge dimer molecules are conjugated with core nanoparticles to deliver signal 1 (antigen presentation). In addition, together with humanized anti-CD28 antibodies, the conjugated HLA-A2-IgG4 hinge dimer molecules deliver signal 2 (costimulation). Subsequently, AIM-np acts as a synthetic APC, directly engaging target T cells through naturally occurring signaling mechanisms. Signal 1 is transmitted by a peptide-loaded HLA class I dimerization fusion protein that presents antigenic peptides to cognate T cell receptors. On the other hand, signal 2 is delivered by monoclonal antibodies against CD28 receptors, which deliver costimulatory signals, also known as “danger signals”, to induce antigen-specific T cell activation and proliferation [118].
The loss of cell surface functional “arms” during DC antigen presentation weakens the interaction between DCs and T cells, disrupting T cell induction [119]. Modification of DCs to enhance their antigen presentation is the most common strategy for T cell activation. “Engineering” or modifying the cell surfaces with synthetic ligands or receptors provides a novel strategy for regulating the interaction between different cell types[120-121]. Lectins are carbohydrate-binding proteins that play an important role in promoting intercellular recognition and adhesion due to their specificity and bond stability[122]. A recent study reported that mannose-modified tumor antigens greatly enhance the ability of DCs to recognize and bind antigens [123]. Therefore, researchers believe that DCs engineered with glycopolymers can specifically attach to T cells through carbohydrate lectin binding, enhancing the stability of DC-T cell binding while promoting T cell activation. Therefore, adding appropriate synthetic glycopolymers to the cell surface is a valuable and effective way to design and optimize cell vaccines [124].