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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5346_Библиотеки_им_академика_М_И_Перельмана
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268 Kai Shi
oncolytic herpes simplex viruses and liposomal doxorubicin. Later, it was found that
losartan depleted the stromal collagen in human ovarian cancer cells by upregulating
the expression of antifibrotic miRNAs such as miR-133 [158].
During tumor progression, CAFs are the major players in the dysregulated collagen turnover leading to tumor fibrosis (desmoplasia) characterized by excessive
collagen depositions in the tumor stroma. It has been shown that CAFs can be reprogrammed from an active myofibroblast state to a quiescent one, such as through
blocking angiotensin II (AngII) signaling that promotes myofibroblast activity or
regulating the main transcriptional myofibroblast phenotype through vitamin
D receptors regulator. Drugs such as angiotensin receptor blocker (ARB) can block
Ang II signaling, inactivate the fibroblast state of CAFs, and reduce αSMA
+
CAFs
levels. Chauhan et al. constructed a compound library based on combinatorial
chemistry and high-throughput screening technology to screen polymer carrier
materials that are highly sensitive to the pH value (6.7) of TME [159]. They have
synthesized a series of polyacetals from polyols and acetals or vinyl ether monomers
through modular reactions of acetal exchange or polycondensation, which were
expected to be degraded under acidic conditions. The ARB was then chemically
conjugated to the screened polymer that is most sensitive to the slightly acidic
TME. And then the generated TME selectively activated polymer (TMA-ARB)
was formulated into nanoparticles via nanoprecipitation, which would provide
ARBs with enhanced tumor permeability and locally responsive release of active
immunoregulators with TME. Compared with free ARB, TMA-ARB reduced
the expression of α-SMA and collagen I, as well as the level of solid stress within
the tumor stroma of mammary tumor-bearing mice, to depress tumor vessels and
increase vascular perfusion, which indicated that TMA-ARB treatment was facilitated to the normalization of the tumor stroma driven by CAFs reprogramming.
RNA sequencing of the mammary tumors in mice showed that TMA-ARB treatment alleviated the expression of hypoxia and TGF-β in the tumor stroma, which
was consistent with the alleviated vascular compression and CAFs activation. Moreover, TMA-ARB treatment also downregulated the gene expression of CXCL13 in
the sorted CAFs, which is mainly induced by the hypoxia and TGF-β signaling and is
responsible for recruiting and inactivating B lymphocytes, as well as CAFs-driven
T lymphocyte repelling. In addition, TMA-ARB treatment also reduced the
expression of IL-10 on both CD45
+
CD45
CD3-B220+in the tumor stroma, which suggested that TMA-ARB
+
CD3+CD8+T lymphocytes and
reversed the immunosuppressive effect of CAFs and the activity of effector lymphocytes. Upon combined with monoclonal antibodies against immune checkpoints of
CTLA-4 or PD-1, TMA-ARB significantly enhanced the number of total leukocytes
+
(CD45
(CD4
) and DCs (CD11b+CD11c+), as well as the ratio of CTLs (CD8+)/Tregs
+
CD25+FoxP3+)andM1(MHCII+)/M2(CD206+) macrophages. Thereafter,
the responsiveness of mice with primary and metastatic mammary tumors was greatly
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improved to the immunocheckpoint blocking therapy.
(2) Degradation of stromal collagen
As the most prevalent component of tumor ECM, collagen is increasingly
becoming an attractive therapeutic target for cancer immunotherapy, and collagenase for collagen degradation is therefore employed to improve the penetration of
immunomodulators and nanotherapeutics into tumor stroma. Inspired by this context, studies have implemented the synergistic treatment of nanotherapeutics and
collagenase.
Oncolytic virus (OV) therapy is a novel and promising therapeutic approach for
tumors that involves selectively infection and lysis of tumor mass. Nevertheless, the
inability to efficiently propagate throughout the tumor stroma and infect target cells
distant from the dosing site has restricted their capacity to achieve consistent therapeutic responses. This limitation seems to be size-dependent caused by the fibrillar
collagen network within the ECM, as nanoparticles of equivalent size manifest the
same extent of intratumoral infiltration, while smaller particles are more widely distributed. Accordingly, concurrent administration of bacterial collagenase led to
enhanced and more homogenous distribution of the oncolytic herpes simplex virus
(HSV) vectors within a xenograft model of melanoma [160].
In view of fact that collagen dominates most of the stroma of pancreatic ductal
adenocarcinoma (PDAC), reaching 12.8% volume compared to 1.4% in healthy
tissues, a liposomal collagenase sized 100 nm has been developed to break down
the dense collagen stroma of PDAC and improve drug penetration into the pancreatic tumor. The liposomal encapsulation protected the collagenase from premature
deactivation and prolonged its release rate at the target site. Intravenous administration of liposomal collagenase allowed a remarkable reduction of fibrotic tissue (5.6%)
as well as tumor burden [161].
In addition to exogenous collagenase, an antifibrotic hormone, relaxin, can also
be used to stimulate collagenase synthesis and down-regulate the secretion of collagen. As a peptide hormone naturally occurring in the human body, relaxin has been
well-demonstrated to inhibit TGF-β1-induced aberrant myofibroblast differentiation and collagen deposition by abrogating the Smad2 phosphorylation via its cognate G protein-coupled receptor, relaxin family peptide receptor 1 (RXFP1).
Besides, an extracellular signal-regulated kinase 1/2 phosphorylation (pERK1/2)
and neuronal nitric oxide synthase (nNOS)/cGMP-dependent pathway are also
involved in this signal transduction. In particular, studies have shown that relaxin
exerted an antihepatic fibrosis effect by reducing the level of α-SMA, collagen,
and tissue inhibitor of metalloproteinases 1 (TIMP-1) in activated hepatic stellate
cells (aHSC). Accordingly, Hu et al. hypothesized that this endogenous repair
269Stromal modulation strategies
270 Kai Shi
mechanism on hepatic fibrosis may be leveraged for the treatment of liver metastasis
via enforced relaxin expression. They developed lipid-calcium-phosphate (LCP)
nanoparticles with aminoethylanisamide (AA) as the targeting moiety, which predominately transfected both metastatic tumor cells and aHSCs within the metastatic
lesion by the loaded pDNA encoding relaxin (pRLN), thereby transforming them
into depots that express relaxin in situ [162]. The local expression of relaxin
deactivated aHSCs and remodeled the stromal milieu in the metastatic lesion, where
both α-SMA expression and collagen content decreased dramatically compared with
PBS control, along with a downregulated prometastatic chemokine of CXCL12 as
well as profibrogenic factors of TGF-β, platelet-derived growth factor (PDGF) and
fibroblast growth factor (FGF). In addition, local enforced expression of relaxin
reactivated intra-metastasis immune milieu, which allowed significant alleviation
of lymphocyte exclusion, downregulation of Th2 cytokine (e.g., IL4, IL6, and
IL10) as well as CCL2 and CCL5 chemokines in metastatic lesions. In contrast,
the expression of Th1 cytokines such as IFN-γ and IL12 were increased significantly.
Accordingly, both Tregs and MDSCs were significantly reduced, along with M2
polarization toward the proinflammatory type I macrophage (M1) phenotype.
Overall, the results of the study suggest the capacity of locally delivering relaxin
by nanoparticles remodeled the immunosuppressive milieu in hepatic metastases
into an immunostimulatory state. The activated immune environment could be further potentiated by the combination with PD-L1 blockade immunotherapy [163].
3.2.2 Hyaluronic acid as a therapeutic target to remodel ECM
As the most abundant nonsulfated glycosaminoglycans in the ECM, hyaluronic acid
(HA) has emerged as another attractive target for remodeling fibrotic tumor stroma. It
is believed that the accumulation of HA predominantly contributed to the reduction
of elasticity and an increase in hydrogel pressure in tumor stroma [164]. In fact, HA
production has been shown to associate with the desmoplastic reaction in PDAC, which
generates inordinately high IFPs and induces vascular collapse, thereby presenting
substantial barriers to perfusion and diffusion of therapeutics [165]. Systemic delivery
of hyaluronidase to ablate existing stromal HA has been explored for normalizing IFP
as well as reexpanding the tumor microvasculature. For example, Zhou et al. reported
the conjugation of recombinant human hyaluronidase (HAase) on the surfaces of
poly(lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG) nanoparticles, which
facilitated the diffusion of nanoparticles and quadrupled their accumulation in 4T1 xenograft breast tumors [166].
In order to enhance tumor infiltration of OVA antigen-specific T effector cells stimulated by the PEI/CpG/OVA nanovaccine, HAase was employed to increase the permeability of nanocarriers to tumor stroma by breaking down the overexpressed HA in
tumor ECM. The combination of nanovaccine with HAase induced a potent immune
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response in the highly aggressive B16-OVA xenograft tumor models, which lead to significantly elevated infiltration of CD8 + T cells as well as higher levels of INF-γ and
TNF-α [167] (Fig. 5).
At present, a PEGylated HAase has entered the later clinical trial which endows
HAase with reduced immunogenicity and prolonged circulation time [168]. To further
improve its tumor specificity, a biocompatible polymer of dextran (DEX) has been
employed to couple with HAase via a pH-sensitive traceless linker. The obtained
DEX-HAase nanoparticles with enhanced enzyme stability against protease and diminished immunogenicity compared to free HAase, exhibit greatly prolonged blood circulation half-life post intravenous injection. Upon passive accumulation in tumors, DEXHAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to
enhanced penetration of oxygen and therapeutic nanoparticles. The largely relieved
tumor hypoxia would promote the therapeutic effect of photodynamic therapy
271Stromal modulation strategies
Fig. 5 The schematic diagram of highly enhanced cancer immunotherapy by combining nanovaccine
with HAase. Subcutaneous administration of PEI/CpG/OVA nanovaccines stimulated immature DCs
(iDCs) into mature DCs (mDCs) and further activated T cells to generate OVA-specific T cells. Pretreatment with HAase by intra-tumoral injection enhanced tumor penetrability and facilitated the
infiltration of OVA-specific T cells generated by the nanovaccine in tumor tissues, ultimately inducing
a significant tumor suppression effect. Reproduced with permission from Guan X, Chen J, Hu Y, Lin L, Sun
P, Tian H, Chen X. Highly enhanced cancer immunotherapy by combining nanovaccine with hyaluronidase. Biomaterials 2018;171:198–206, copyright © 2018 Elsevier Ltd.
272 Kai Shi
(PDT), accompanied by the reverse of the immunosuppressive TME to boost immune
checkpoint blockade therapy [169].
3.3 Targeting cancer-associated fibroblasts
3.3.1 Depletion of CAFs to normalize tumor stiffness
The extracellular matrix (ECM), mainly generated from CAFs and accumulated in the
TME, can form a dense physical barrier and elevate the hydraulic pressure of the tumor
interstitium, thereby hindering the effective penetration of nano-immunomodulators
into deeper tumor tissues. To this end, Ernsting et al. synthesized a conjugate of docetaxel
(DTX), polyethylene glycol (PEG), and acetylated carboxymethyl cellulose, termed as
Cellax-DTX, which could self-assemble into nanoparticles with a size of 120 nm an
aqueous solution [170]. In the PDA xenografts derived both from highly stromal primary
patients and metastatic mouse models, more than 90% of Cellax-DTX nanoparticles
passively accumulated in SMA
populations and therefore decreased stroma density. As a result, the perfusion of tumor
tissues by nanoparticles elevated more than 10-folds, and effectively alleviated tumor
progression and metastasis.
In a recent study undertaken by Fang et al., a composite nanoparticulate system with
the ability of programmable drug release, termed G(TM)PPSP, was developed for TME
remodeling and treatment of mammary cancer [171]. In this nanomedicine delivery
system, an angiotensin II type 1 receptor (AT
loaded into gelatin nanoparticles, and paclitaxel (PTX) was linked with platinum
nanoparticles (PtNPs) via a diselenide bond of dual redox responsiveness, and finally,
these two nanoparticles were covalently coupled together to form a composite nanoparticle with a size of about 214 nm. The tumor stroma responsive release of TM from gelatin nanoparticles was induced by the gelatin degradation, which is attributed to the
MMP-2 secreted by CAFs. Then intracellular cytoplasm release of PTX was achieved
due to the cleavage of diselenide linkage triggered by high levels of reactive oxygen species (ROS) or glutathione in tumor cells. Therefore, the designed nanoparticle delivery
system allowed the programmable release of both agents in the correct location of the
tumor tissues. The downregulation of TGF-β by TM leads to ECM depletion, which
is conducive to the penetration of GTMPPSP into deep tumor stroma. Concomitantly,
cytotoxic agents-mediated chemotherapy and PtNPs-mediated photothermal therapy
jointly suppressed the progression of 4T1 tumors. In vivo results of tumor suppression
suggested that the mechanism by which G(TM)PPSP effectively inhibit tumor growth
was through the destruction of ECM and downregulation of the immunosuppressive factor TGF-β derived from CAFs, thereafter promoting the infiltration of CD4
T cells into tumor stroma and thus alleviating the immunosuppressive TME. On the
other hand, PtNPs mediated PTT induced apoptotic tumor cells to release antigens such
+
CAFs, which lead to the depletion of the stromal cellular
R) antagonist of telmisartan (TM) was
1
+
and CD8
+
as calreticulin and activate the immune responses of specific T lymphocyte, thereby pro-
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moting immune activation at tumor sites.
Cun et al. also reported a multifunctional nanoparticle with a switchable size that
could codeliver gemcitabine (GEM) and 18β-glycyrrhetinic acid (GA) for TME remodeling promoting deep tumor penetration [172]. The complex nanocarriers, termed as
DGL/GEM@PP/GA, were designed by conjugating GEM to dendritic grafted poly-
L-lysine (DGL), which is a kind of dendrimer and can self-assembly with a smaller size.
Through the substrate peptide linkage of MMP-2, DGL was coupled with nanoparticles
of PEG-PCL that were preloaded with GA. Upon systemic administration in the mice
with pancreatic ductal adenocarcinoma and mammary cancer models, GEM-coupled
small nanoparticles were released from the complex nanocarriers due to the enzymolysis
of overexpressed MMP-2 in the tumor stroma. The dissociated DGL particles could penetrate the deep part of the tumor with the help of their smaller size and then release GEM
intracellularly to kill tumor cells. While the residual larger particles (PP/GA) loaded with
GA could accumulate around tumor-stromal vessels and be preferentially taken up by
CAFs due to their poor tissue permeability, thereby downregulating the secretion of
Wnt16, a signaling molecule involving DNA damage response program (DDRP) that
can promote the proliferation and invasion of adjacent cancer cells, leading to tumor
metastasis and acquired resistance against chemo/immunotherapy. Targeting CAFs with
GA resulted in effective suppression of GEM-induced CAFs activation, as evidenced by
the decrease in expression of α-SMA and collagen in tumor stroma.
In recent years, Oncolytic adenovirus (OAd) represents a promising therapeutic vector for solid tumors, which can achieve improved antitumor outcomes through dual
mechanisms of specifically lysing cancerous cells and inducing antitumor immunological
response of the body. Nonetheless, clinical trials of tumor treatment employing OAds
have so far yielded encouraging yet unsatisfactory results. The limited efficacy has been
reported to be related to the nonspecific tumor localization, poor intratumoral spread,
and viral immune responses. Therefore, it is urgent to adopt new strategies to overcome
these obstacles that hinder the successful clinical application of OAds, including specific
depletion of CAFs that hinder the effective penetration of the virus in the tumor stroma,
and suppression of virus epitope dominance which accelerates virus clearance. In the
work of Sostoa et al., these limitations were addressed by arming the OAds with bispecific
T cell engager (FBiTE) against FAP, which was constructed through coupled an antiCD3 scFv with an anti-FAP scFv. The expression of FBiTE could redirect the infiltrating
+
CD3
effector T cells to FAP+CAFs, thereby enhancing virus diffusion as well as T cellmediated cytotoxicity against tumor stroma, to achieve the purpose of improving immunotherapeutic outcome [173].
Contrary to the initial belief that there is negligible FAP expression in normal adult
tissues, recent studies indicated that FAP-positive fibroblasts are also present in the placenta, uterus, embryos as well as bone marrow. Systemic depletion against FAP-positive
273Stromal modulation strategies
274 Kai Shi
fibroblasts would likely cause severe cachexia, amyotrophy, myelotoxicity, and even
mortality [174]. Tran et al. have reported that targeting FAP with T cells transduced using
FAP5-CAR could cause cachexia and fatal osteotoxicity because a certain amount of
FAP is also expressed in pluripotent stem cells (BMSCs) [175]. These findings raised
doubts about anti-FAP-based treatment and have hindered the development of related
clinical research to a large extent. Therefore, there is an urgent need for a new therapy
that can selectively deplete CAFs from tumor stroma without causing systemic toxicity.
In recent years, near-infrared photoimmunotherapy (NIR-PIT) has been introduced
as a new type of targeted phototherapy, which employs cell-specific monoclonal antibodies that are coupled with photosensitizers. Watanabe et al. conjugated IRDye700DX
to FAP monoclonal antibody (mAb-IR700) to target CAFs [176]. As a local control
treatment rather than a systemic therapy, mAb-IR700 only works when it is irradiated
with near-infrared light and induces significant cytotoxicity in tumor stromal cells that
specifically express FAP. Targeting CAFs by specific labeling of FAP may be a therapeutic
target for regulating tumor immunosuppressive microenvironment in the future, and it
also provides a safe strategy for the control of epithelial malignant tumors. To this end,
Zhen et al. provide a novel strategy of photoimmunotherapy based on the nanoparticle,
which can address the need. They loaded photosensitizer (ZnF16Pc) into apolipoferritin
nanocarrier with a cage-like structure, and the surface of which was further conjugated to
a FAP-specific single-chain variable fragment (scFv) [177]. When the systemic application, the constructed nanoconjugates were able to locate CAFs specifically in tumor
stroma mediated by FAP-scFv. The following light irradiation resulted in the ablation
+
of FAP
stromal cells while without detectable damage to healthy tissues, which is attributed to confined action. The mechanism of action underlying this combination treatment likely destroys ECM and inhibits the secretion of CXCL12 from FAP
+
fibroblasts, consequently improving the infiltration of CD8+T cells and activating their
function of specifically recognizing and killing tumor cells.
3.3.2 Blockade of the crosstalk between CAFs and tumor cells
Recent work by Feig et al. suggested that CXCL12 is a key chemokine to inhibit the
effective infiltration of T cells. They showed that, like human patients with pancreatic
ductal adenocarcinoma (PDA), KPC transgenic mice bearing orthotopic PDA failed
to respond effectively to both anticytotoxic T-lymphocyte-associated protein 4
(α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1), two kinds of typical
immune checkpoint blocking antibodies used for activating infiltrating cytotoxic
T lymphocytes (CTLs) [131]. Further analysis revealed that the PDA stroma was characterized as absent of T cell infiltration, and most cancer cells were binding with
CXCL12 (CXC motif ligand 12), a chemokine mainly derived from fibroblast activation
protein (FAP) expressed CAFs (FAP
+
CAFs). Based on the findings, a specific small mol-
ecule CXCL12 receptor (CXCR4) inhibitor, AMD3100, was administrated, which
greatly led to improved infiltration of CTLs around tumor cells, and uncovered the cura-
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tive efficacy of immune checkpoint blocking therapy.
Inspired by the work, Miao et al. proposed to make chemokines and immune check-
point traps expressed locally and transiently in tumor stroma for the treatment of PDAC.
A plasmid DNA encoding single-domain antibody mimics against CXCL12 and PD-L1,
so-called protein traps, was first designed and encapsulated into the cationic protamineliposome (LPD) vectors [178]. Results indicated that both tumor cells and fibroblasts
adjacent to stromal vessels were the main sites for vector distribution and gene expression.
In the case of pPD-L1 trap monotherapy, the antitumor effect is still limited in the KPC
model, as indicated by the poor infiltration of CD3
+
T cells and their distribution on the
edge of the tumor niche, rarely inside the tumor mass. Concomitantly, tumor-infiltrating
myeloid cells such as Tregs, MDSCs, and TAMs were recruited via the CXCL12/
CXCR4 axis and accumulate into the tumor stroma at high levels, which directly or indirectly mediate suppression of CD3
+
T effector cells. Upon synergistically neutralizing
CXCL12, the infiltrations of these immune suppressive lymphocytes were significantly
reduced, and thereafter facilitating an improved increase in the infiltration of CD3
T cells into tumor tissues. On the other hand, by detecting changes in the levels of cytokines in local tumor tissues, it was found that the pCombo trap group led to a significant
decrease in the levels of IL-4 and IL-10, as well as a significant increase in the levels of
IL-12α and TNF-α and IFN-γ. The phenotype switches from Th2 to Th1 indicated that
the immunosuppressive microenvironment has been remodeled into an immunostimulatory one, thereby activating the recruited lymphocytes as effector cells, and leading to enhanced CTLs-mediated cytotoxicity. In particular, neutralization of CXCL12
also remolded the extracellular matrix (ECM) by reducing αSMA and collagen content,
which lead to the normalization of tumor vasculature, and thereby improving
intratumoral diffusion and increased perfusion of nanoparticles (Fig. 6).
The crosstalk between chemokine receptor CXCR4 that is expressed in cancer cells
and its ligand CXCL12, secreted by hepatic stellate cells (HSC), plays a crucial role in the
hepatic metastasis of colorectal cancer (CRC) as well as many other cancers. It has been
shown that HSC located in the Disse cavity between hepatic sinusoidal endothelial cells
and hepatocytes can secrete a large number of endogenous CXCL12, which not only
recruit immunosuppressive lymphocytes including Tregs and MDSCs to the inflammatory area but also induce CXCR4-positive CRC cells to migrate along the concentration
gradient of CXCL12 and invade the liver tissue. To this end, Goodwin et al. developed a
lipid calcium phosphate nanoparticle (LCP) to deliver plasmid DNA encoding the
CXCL12 trap into hepatocytes, which can produce transient expression of target protein
trap in the liver within 4 days [179]. The results showed that blocking the CXCL12/
CXCR4 axis not only significantly reduced the occurrence of CRC hepatic metastasis
but also avoided the toxicity of off-target associated with systemic application of chemokine therapy. Further analysis of the effects of blocking CXCL12 expression on the
275Stromal modulation strategies
+
276 Kai Shi
Fig. 6 Illustration of the mechanisms underlying LPD nanoparticles targeted CAFs for the immunotherapy of PDAC. Plasmids encoding PD-L1 and CXCL12 trap were encapsulated into nanoparticles.
Local and transient delivery of the encapsulated plasmids reduced their systemic toxicity and allowed
accumulation in perivascular cells. The CXCL12 capture protein secreted from perivascular cells promoted effective capture of CXCL12 chemokines, which not only directly reduced infiltration of immunosuppressive cells (such as MDSCs and Tregs) through the CXCL12/CXCR4 axis but also inhibited the
expression of PD-L1 by regulating the MAPK pathway. Reproduced with permission from Miao L, Li J, Liu
Q, Feng R, Das M, Lin CM, Goodwin TJ, Dorosheva O, Liu R, Huang L. Transient and local expression of
chemokine and immune checkpoint traps to treat pancreatic cancer. ACS Nano 2017; 11(9):8690–8706,
copyright © 2017 American Chemical Society.
immune cell population (including MDSCs, Tregs, and CD8+T cells) in the liver stroma
showed that pCXCL12 trap treatment significantly reduced the number of immunosuppressive lymphocytes such as MDSCs and Tregs in the hepatic stroma. It should be noted
that although a large number of CD8
+
T cells are found in the liver of the untreated CRC
group, most of their cancer-specific killing functions have been neutralized by the immunosuppressive MDSCs and Tregs populations.
3.3.3 Reprogramming CAFs to an immunosupportive state
Given the research work of Huang’s research group, it is shown that genotoxic chemicals
caused DNA damage of CAFs and thereafter induction of Wnt16 secretion contributed
to the drug resistance in neighboring cancer cells [180]. Many natural antifibrotic compounds with low toxicity, such as quercetin, puerarin, α-mangostin [181], and
fraxinellone [182], can downregulate the expression of Wnt/β-catenin in a variety of cell
lines, thereby reversing tumor resistance to cytotoxic chemicals. Hu et al. encapsulated
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quercetin phosphate into targeted lipid calcium phosphate nanoparticles (LCP) with high
loading capacity (26.6% w/w) and small particle size (about 35 nm) [183]. The systemic
administration of quercetin-loaded LCP could effectively remold the TME, as
manifested in significantly reducing α-SMA+ fibroblasts and collagen in the tumor
stroma, to enhance the penetration of subsequently administered cisplatin-loading
nanoparticles into the tumor niche. When combined with cisplatin nanoparticles, a significant downregulation of Wnt16 expression could be observed in the urothelial bladder
carcinoma model that is rich in the stroma.
Xu et al. formulated puerarin into a nanoemulsion (nanoPue) to selectively attenuate
desmoplastic reaction in tumor stroma through downregulation of ROS production in
the activated myofibroblasts [184]. As expected, targeted inactivation of CAFs obviously
attenuated the levels of Th2 cytokines including IL-4, IL-6, IL-10 as well as IL-13 in the
tumor stroma, thereby resulting in elevated tumor infiltration of specific T lymphocytes.
Among them, CD8
+
T cells, in particular, have been more strongly promoted, showing a
twofold increase upon depletion of tumor-stromal barrier by nanoPue. In addition, the
concomitant downregulation of C-C motif chemokine chemokines (CCL2 and CCL5)
together with the attenuated intratumoral Th2 cytokines further remold the immunosuppressive TME by preventing the immunosuppressive inflammatory cells such as Tregs
and MDSCs from recruitment and infiltration into tumor stroma and promoting the
polarization of TAMs toward the proinflammatory M1 phenotype. Moreover, the
remolded immunostimulatory TME allowed nanoPue to synergize PD-L1 blocking
treatment in the desmoplastic tumor model of triple-negative breast cancer (TNBC).
To reverse immunosuppressive TME of desmoplastic melanoma primarily mediated
by TGF-β, Hou et al. developed a nanoemulsion to targeted delivery of an antifibrotic
agent, fraxinellone, to CAFs [185]. Upon systemic administration, the small particle size
of 145 nm enabled the formulation to efficiently accumulate in the tumor site and was
internalized into CAFs and tumor cells. With the elimination of TAFs and ECM, the
TME was remodeled by the treatment, as evidenced by an increase in cytotoxic effector
cells of CD8
+
T cells and NK cells, along with a decrease in immunoregulatory Bregs and
MDSCs. Besides, the treatment enhanced the Th1 cytokine of IFN-γ and impeded the
expression of TGF-β, CCL2, and IL-6 that are predominantly immunosuppressive. Furthermore, targeting the delivery of the antifibrotic agent boosted the antitumor immune
response of the tumor-specific peptide vaccine against BRAFV600E, which is specifically
overexpressed in BRAF-mutant melanoma.
277Stromal modulation strategies
3.3.4 Engineered nanovaccine against stromal antigens
As a type II membrane-bound serine protease, fibroblast activation protein (FAP) usually
exhibits the activities of dipeptidyl peptidase and collagenase [186]. It has been found that
the expression of FAP is highly limited in CAFs of most common epithelial carcinoma,
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