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].