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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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258 Kai Shi
delay tumor progression and have failed in a few clinical human trials. The study by
Kumar et al. revealed that CSF1 derived from tumor cells lead to the downregulated
expression of chemokine (such as CXCL1) specific to granulocyte in CAFs, thereby
limiting the recruitment of these cells to tumor stroma [109]. The blockade of
CSF1R reversed this crosstalk and triggered the accumulation of immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the
TME. Accordingly, the combination of CSF1R inhibitor that targets TAMs and
selective CXCR2 antagonist could prevent PMN-MDSC from infiltrating tumors,
and when further synergistic with the anti-PD-1 antibody, it can significantly
improve the effect of immunotherapy. Yu et al. also demonstrated in a mouse model
of pancreatic ductal adenocarcinoma (PDAC) that the inhibition signaling mediated
by CSF1R could functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. In addition, CSF1R
blockade also upregulated T-cell checkpoint molecules, including PDL1 and
CTLA4, thereby restraining beneficial therapeutic effects [110].
(2) NKs
As an important effector cell in innate immunity, natural killer cells (also known
as NK cells or large granular lymphocytes) are a subset of cytotoxic lymphocytes
homologous to T and B cells and have strong antitumor function [111]. It is believed
that NK cells mainly exert their killing effect through the following ways:① directly
release cytotoxic particles such as perforin and granzyme through exocytosis, and
activate the caspase pathway to induce apoptosis of target cells; ② express factor
associated suicide ligand (FasL) and tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) to induce programmed apoptosis of target cells; ③ synthesize and
secrete a variety of cytokines such as IFN-γ, TNF-α and IL-3 to exercise cytokinemediated killing effects [112, 113].
Balsamo et al. provided evidence for the immunosuppression initiated by metastatic melanoma derived fibroblasts [114]. It was observed that through the crosstalking mediated by prostaglandin E2 (PGE2) secretion, CAFs strongly mediated
the dysfunction of NK cells, including cytotoxicity and the production of cytokines.
Consequently, the proliferation of NK cells activated by IL-2 was significantly
inhibited, which was manifested by the downregulation of natural cytotoxic receptors
such as NKp44, NKp30, DNAM-1 specifically expressed on their cellular surface, as
well as attenuated production of cytolytic granules in NK cells. Furthermore, CAFseducated NK cells lead to an impaired immune killing effect against melanoma target
cells. The study by Li et al. provided evidence that the proinflammatory cytokine
PGE2 secreted by CAFs plays a dominant role in regulating the activity of NK cells
[115]. Fibroblasts derived from colorectal carcinoma mediated the NK cell anergy
in a variety of ways, including inhibition of NK receptor activation, the expression
of perforin and granzyme B, and the production of cytokines such as TNF-α and
IFN-γ. In contrast, normal skin-derived fibroblasts caused negligible changes in the
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phenotype and functions of NK cells.
(3) MDSCs
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells that originated from bone marrow precursors
[116]. They migrate to tumor inflammation sites under the chemotaxis and regula-
tion of stromal cells, and then differentiate into macrophages, DCs and granulocytes
[117]. Under normal conditions, these precursor cells eventually differentiate into
macrophages, DCs and granulocytes under the chemotaxis and regulation of stromal
cells. However, under abnormal pathological conditions such as chronic inflammation and cancer, their differentiation suffers from partial impediment and leads to an
accumulation of immature ones, which usually exhibit features of immunosuppression rather than immunostimulation [118].
Studies have identified that monocytes were recruited by CAFs via the stromal
cell-derived factor SDF-1a/CXCR4 axis, and then induced to differentiate into
MDSCs through activation of STAT3 that was mediated with IL-6. As a result,
CAFs primed monocytes impaired the proliferation of T lymphocytes, as well as
their immunostimulatory phenotype and function [119]. In addition, it was found
that CD11b
+
myeloid cells, similar to MDSCs in phenotype and function, were
mainly distributed within the peritumoral stroma, and their densities were positively
correlated with the CAFs abundance and progression of hepatocellular carcinoma
(HCC) in vivo. Accordingly, the combination of immunotherapy and Antagonism
of STAT3, SDF-1a or IL-6 may provide a candidate strategy for depleting the
immunosuppressive MDSCs in HCC.
Mace et al. also confirmed that pancreatic stellate cells (PSC), a subset of pancre-
atic cancer-associated fibroblasts, play an important role in driving immune escape in
pancreatic cancer, extend the evidence that STAT3 acts as a driver of stromal immunosuppression [120]. The luminex analysis showed that PSC, but not human fetal
primary pancreatic fibroblasts, could secrete MDSC induced cytokines including
IL-6, VEGF and M-CSF, as well as chemokine of SDF-1 and CCL2 (MCP-1).
As the main source of CCL2 secreted, FAP
+
CAFs could enhance the recruitment
and infiltration of MDSCs in hepatoma stroma through the fibroblastic signaling
pathway of STAT3-CCL2 [121]. Upon primed with a conditioned medium of
PSC supernatants or IL-6/GM-CSF, peripheral blood mononuclear cell (PBMC)
could differentiate into CD11b
+
CD33+CD15+polymorphonuclear neutrophil
(PMN), a phenotypic subset of MDSCs that functionally suppressed the proliferation of autologous T lymphocytes.
(4) DCs
Dendritic cells (DCs) are considered to be effective antigen-presenting cells
(APCs), with the remarkable characteristic of stimulating naive T cells. Accordingly,
259Stromal modulation strategies
260 Kai Shi
they are also key promoters of the immune response, in addition to playing a major
role in inducing antitumor immunity [122]. In accordance with their ability to stimulate T cell proliferation, DCs are typically divided into immature dendritic cells
(imDCs) and mature dendritic cells (mDCs). Among them, mDCs may induce
Th1-type immune responses through the activation of TSA-specific CTLs [123].
There is a complex crosstalk between CAFs and DCs, and which is highly related
to the immune response of T cells. Tolerogenic DCs (tDCs) is a type of immature
DCs that induces specific immune tolerance. This subset of DCs is characterized by
elevated expression levels of coinhibitory molecules (such as CTLA-4, PD-1) and
immunosuppressive factors (such as IL-10 and IDO), as well as deficiency in
IL-12 secretion. Accordingly, they present antigens to the initial T cells and induce
the proliferation of CD4
+
CD25+Tregs, thus inducing anergy in effector T cells
[124]. The study by Khosravi-Maharlooei et al. showed that DCs lost the ability
to stimulate the proliferation of CD4
+
and CD8+T cells after priming with mouse
skin-derived fibroblasts [125]. Moreover, the immune activation function of DCs
could not be restored even if stimulated by CpG ODN, an agonist of Toll-like
receptor 9 (TLR9). One possible explanation for the decreased DCs stimulation
ability induced by fibroblasts is the increased expression of antiinflammatory cytokines and the decreased expression of proinflammatory cytokines. The inaptitude of
the immune stimulatory ability of DCs induced by fibroblasts may be attributed to
the elevated expression of antiinflammatory cytokines such as IL-10 and IDO and
the reduced expression of proinflammatory cytokines such as IL-12p70 in DCs.
Generally, IL-10 induces anergy of T lymphocytes, especially CD4
+
effector and
memory T cells. Indoleamine 2,3-dioxygenase (IDO) is a heme enzyme that mediates the catabolism of tryptophan. It can inhibit the proliferation of T cells by local
consumption of tryptophan and production of canine tryptophan, a by-product of
the pathway involving kynurenine metabolism and is cytotoxic to T cells [126].In
addition, the production of IFN-γ by DCs requires autocrine IL-12 signaling, and its
downregulation will hinder the stimulation state of DCs. Cheng et al. also showed
that CAFs derived from hepatocellular carcinoma induced Tregs to be enriched in
tumor stroma and overexpress IDO by highly secreting IL-6, which in turn lead to
T cell anergy and proliferation of Tregs, and mediated the immune tolerance and
immunosuppression of tumor cells [127]. The employment of IDO antagonists,
antiSTAT3 and anti-IL-6 antibodies could reverse the immunomodulatory effects
of CAFs on DCs.
2.3.6 Regulatory effects of CAFs on adaptive immune cells
(1) T cells
Cytotoxic T lymphocytes (CTLs) are a subset of T cells with CD8
marker and restricted by MHC class I molecules, which are responsible for
+
surface
eliminating cancer cells in the adaptive immune system [128]. Upon activation fol-
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lowing recognition of tumor antigens presented by APCs coupled with the simultaneous acquisition of synergistic stimulation signals provided by costimulatory
molecules such as B7/CD28 and CD40/CD40L, CD8
+
T cells will proliferate
and differentiate into functional CTLs. Following the identification of tumor antigens, CTLs perform their tumor-killing function by secreting perforin, granzymes,
and IFN-γ [129]. Overall, tumor cell evasion of immune surveillance primarily
occurs when CD8
+
CTLs are ineffectively activated.
CAFs can act on effector T cells throughavarietyofwaystoregulatetumor
immunity. CAFs can reprogram effector T cells through the production of soluble
cytokines such as IL-10, TGF-β and VEGF , or prostaglandin E2, dipolyoxygenase
and arginase [130]. In the mouse model of pancreatic cancer, even in the presence
of infiltrating CD8
+
T cells, the antibody antagonists of cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) and programmed death ligand-1 (PD-1) could not
exert their antitumor functions. However, when CAFs were depleted from tumor
stroma, it was found that CTLA-4 and PD-L1 antibodies restored their
corresponding functions, mainly due to CAFs-secreted CXCL12 that could
directly induce T cell anergy, restrict T cell recruitment and spread in tumor
stroma [131].
(2) Tregs
Tregs are a group of lymphocytes that negatively regulate the body’s immune
response. They typically play a p ivotal role in the maintenance of autoimmune
tolerance, in addition to being considered immunosuppressive [132].Tregsnegatively regulate the immune response primarily by three mechanisms: (1) induction of T cell apoptosis through cell-cell interactions; (2) suppression of immune
responses through secretion of cytokines, for instance, TGF-β and IL-10; (3)
release of perforin and granzymes in order to kill CTLs, monocytes and DCs
directly [133].
CAFs can also exert immunosuppressive effects by affecting the function of
Tregs. In prostate cancer, CAFs-derived TGF-β promoted the differentiation of
+
CD8
T cells into Tregs, which inhibited the immune function of CD4+T cells
[134]. Studies have shown that after DNA damage-related treatments such as che-
motherapy and radiotherapy, human ovarian fibroblasts could overexpress and
secrete WNT16B into the tumor stroma [135]. The fibroblast-derived WNT16B
could lead to the accumulation of β-Catenin and secretion of IL-10 and TGF-β
in dendritic cells, thereby contributing to the differentiation of Tregs. Nevertheless,
some studies have shown that depletion of αSMA + myofibroblasts resulted in a
significant elevation in the ratio of regulatory T-cell/effector T-cell (Treg/Teff )
and expression of CTLA-4, which is believed to lead to the suppression of immune
surveillance in PDAC [136].
261Stromal modulation strategies
262 Kai Shi
3. Stromal modulation strategies with nanotechnology
to improve immunotherapy
Owing to the fast-paced growth of nanomaterials and the comprehensive understanding of stroma-mediated immunotherapy in recent yea rs, nanoparticles have been
put to extensive use for regulating the tumor stroma and improvement of tumor immunotherapy: (1) Synthetic and naturally derived nanoparticles, such as lipid, protein,
polymer, and inorganic materials, have unique physicochemical properties, enabling
them to serve as drug carriers that meet medica l needs. The nano-formulated immunomodulators endow them with improved pharmacokinetics and pharmacodynamics
in vivo without changing their pharmacological activity [137]. (2) Because the size of
the nanoparticles is similar to that of pa thogens, they can mimic the endocytosis of
pathogens into endosomes, followed by promoting the presentation of antigens
through the MHC-I pathway in a "cross-presentation" manner. This is more likely
to induce a long-term, effective, tumor-specific CTL response in comparison to the
free antigen. (3) Nanoparticles are also capa ble of safeguarding biomacromolecular
immunotherapeutic components (e.g., peptide antigens, nucleic acid vaccines, and
DNA adjuvants) from premature degradation in the biological environment, accordingly e nhancing their stability in vivo, while also being capable of sustained release of the
antigen, helping to augment the intensity of the immune response [138]. (4) With the
use of unique attributes of the tumor stroma, for instance, hypoxia, weakly acidic pH
and tumor pressure gradie nt as well as the n atureofECM,itispossibletodesignand
develop nanoparticles that have different types of environmental stimuli responses to
precisely deliver the immunotherapeutic ingredientstoparticularcellsornoncellular
components in the stroma to improve the immune response [139]. (5) Nanoparticles
can be easily subjected to functional chemical or biological modifications. Tumor
stroma and immune cells typically overexpress or specifically express particular c ellular
surface molecules as well as secretory factors, providing a general idea for the functional
design of nanoparticles. Targeting these cell markers has the potential to augment the
uptake of nanopa rticles by the tumor stroma and lower adver se effects on normal cells.
(6) The efficacy of single immunotherapy for primary solid tumors is usually constrained. Radio/chemothera py can kill some tumor cells in advance, leading to exposure of lots of tumor antigens in the TME, which can mobilize more i mmune effector
cells f or remodeling the immunosuppressive status of the TME. Nanoparticles are capable of combining immunomodulators with chemical drugs, phot osensi tizers, and
photothermal materials, which allows the combination of immunotherapy with chemotherapy, photodynamic therapy, and photothermal therapy to achieve synergistic
antitumor effects [140].
3.1 Targeting tumor neovascularization
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3.1.1 Inhibiting angiogenesis for vasculature normalization
The abnormality of the tumor vascular system is manifested as heterogenous vessel diameter, tortuous and distribution, as well as insufficient blood and oxygen supply, and which is
associated with hypoxia, pH reduction, interstitial pressure enhancement immunosuppression in the tumor stroma. Therefore, the normalization of tumor vasculature may
be a way to modulate tumor immune response [141]. One of the important considerations
for the success of immunotherapy is the dosage of antiangiogenic agents. Unlike normal
blood vessels, tumor vasculatures are abnormally tortuous and branched, which forth a
challenge in the effective diffusion of therapeutic moieties within tumor stroma [142].
In view of the fact that overexpressed and secreted VEGF-A in the tumor stroma contributes to the abnormalities of the tumor vascular system, current antiangiogenesis therapies
predominantly target this molecule or its receptor [143]. Antivascular drugs mainly include
tyrosine kinase inhibitors (TKI) that target proangiogenesis related receptors to block their
signaling pathways, such as sunitinib and sorafenib, as well as monoclonal antibodies such as
bevacizumab that directly target VEGF or VEGFR in circulation. Nevertheless, the tumor
vascular network exposed to a high dose of VEGF antagonist often suffers destruction,
which aggravates the hypoxia in TME and prevents TAMs from polarizing toward the
inflammatory phenotype. In addition, the absence of a vascular system further impaired
the diffusion of immune effector cells within the tumor stroma [144]. Accordingly, it is
important to normalize the tumor vasculature, rather than completely destroy it. The rational use of antivascular drugs to promote the normalization of tumor vascular is expected to
improve the immunosuppressive TME, which is manifested in the enhanced number and
function of DCs, reduced the proportion of Treg and MDSCs within tumor stroma and
circulation, as well as enhanced the intratumoral infiltration of CD4
T cells [145].
To explore the effect of tumor vascular normalization on the delivery of
nanomedicine, Chauhan et al. carried out a VEGFR2 blockade to modulate the penetration rates of quantum dot-based nanoparticles in orthotopic mammary tumors. They
showed that blocking VEGFR2 to repair abnormal vessels in breast tumors could reduce
the size of pores on the blood vessel wall and alleviate the interstitial fluid pressure in
tumors, thus allowing smaller nanoparticles ( 12 nm) to enter them more rapidly. Concomitantly, the increase in steric hindrance and hydrodynamic disturbance associated
with the reduction of vascular wall pores hindered the transport of larger particles
(125 nm) [146]. Their results indicated that the restoration of dysfunctional tumor vasculature could rebuild the pressure gradient between the intravascular and interstitial
spaces, which is essential for the delivery of nanomedicine into solid tumors. Although
nanoparticles smaller than 10 nm in size maximally benefited from tumor vascular normalization for enhanced nanomedicine delivery, their applicability is severely limited due
+
and CD8
263Stromal modulation strategies
+
264 Kai Shi
to the too-small particle size. It was later demonstrated that tumor revascularization
enhanced the transvascular delivery of medium-sized nanoparticles up to 40 nm [147].
Upon entering the tumor stroma, however, smaller nanoparticles experience a lower
diffusional hindrance, resulting in a more homogeneous distribution within the tumor
interstitium. The findings suggested that antiangiogenesis-based nanoparticles can be
designed into size-tunable to meet the multistage delivery of nanomedicines in solid
tumors.
Copper chelation has been proven to be an effective antiangiogenic treatment strategy
for breast cancer. Zhou et al. synthesized a coil-comb block copolymer capable of chelating coppers, in which poly-
L-histidine (PHis) and RGD-coupled poly-γ-glutamic acid
(γ-PGA) served as hydrophobic and hydrophilic motifs, respectively. In the neutral systemic circulation, the polymers could self-assemble into multifunctional nanoparticles
due to aggregation of PHis segments via hydrophobic interaction and therefore load
resiquimod (R848), an agonist of Toll-like receptor 7/8 (TLR7/8). Upon intravenous
administration, the nanoparticles could reach the targeted tumor tissues via specific binding of RGD peptide with integrin αvβ3 that is overexpressed on tumor neovasculature,
thereby exhibiting strong antiangiogenic activity. In addition, the acid-triggered release
of R848 induced the maturation and activation of plasmacytoid dendritic CAL1 cells,
indicating their ability of immune activation [148].
3.1.2 Combination of vascular normalization and immunotherapy
We have known that the success of immunotherapy depends on the recruitment and
expansion of immune effector cells (especially CTLs) in the TME to generate an immune
response. The recruitment of T cells into tumor stroma is a multistep process that
involves, as a first step, their rolling to the specific HEVs dependent on the adhesion molecules, such as E-selectin, ICAM-1, and VCAM-1 on the surface of vascular endothelial
cells. Then come integrin-mediated sturdy arrest and transendothelial cell migration. The
study of Schmittnaegel et al. revealed that a combined blockade of angiopoietin-2
(ANG2) and VEGF-A by a bispecific antibody (A2V) normalized the remaining blood
vessels and facilitated the extravasation and perivascular accumulation of activated CTLs.
Consequently, the promotion of vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes was achieved [149]. Whereas perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell
death ligand 1 (PD-L1) in tumor endothelial cells. Allen et al. also observed in mouse
models of breast, brain, and pancreatic tumors that the application of antiangiogenesis
treatment increased the expression of PD-L1 on tumor endothelial cells, thereby
resulting in the initiation of PD-1/PD-L1 mediated immunosuppressive pathways and
thus anergy or exhaustion of T cells. Upon combined application of anti-VEGFR2
and anti-PD-L1 treatments induced the formation of HEVs, which promoted lymphocyte infiltration and activity through activating the signaling of lymphotoxin β receptor
(LTβR) [150]. In addition, the combined treatment can reduce the dosage of immune
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checkpoint inhibitors, thereby reducing the toxicity risk of immunotherapy and improving the quality of life and prognosis of patients.
As one of the promising nanocarriers, gold nanoparticles (AuNPs) possess excellent
performance for drug delivery and inherent antitumor activities. Huang et al. synthesized
gold nanoparticles targeting folic acid receptor which was stabilized by an amphiphilic
block copolymer of poly-(ethylene glycol)-b-poly (diethylaminoethyl acrylate) (PEGPDEAEA) [151]. The studies have found that in addition to inhibiting tumor angiogenesis, gold nanoparticles normalize the tumor vascular system by increasing the expression
level of VE-cadherin, as well as pericyte coverage and strengthening tight junctions,
thereby attenuating vascular permeability, improving vascular perfusion, and relieving
tissue hypoxia. The normalized tumor vasculature system increased the infiltration of
+
CD3
CD8+T lymphocytes, enhanced the immunotherapy response, and also inhibited
tumor metastasis. Moreover, gold nanoparticles elevated the expression and secretion of
semaphorin 3A (SEMA3A) in cancer cells to further suppress the Smad 2/3 signaling in
human umbilical vein endothelial cells (HUVECs).
To combine vascular normalization therapy and tumor cell metabolic treatment, Jetlagged nanoparticles with a cationic core of chitosan were constructed to load apatinib
(APA) and lonidamine (LND), respectively, in which APA acted as an antiangiogenic
agent for vascular normalization therapy by specifically blocking the ATP-binding sites
of VEGFR2, while LND could be employed for restraining the lactic acid efflux and
alleviating acidosis by downregulating the monocarboxylic acid transporter receptor 4
(MCT4). Then the secondary assembling of negative hyaluronic acid and polystyrene
sulfonate were following to ensure the stable and safe delivery of nanoparticles in vivo.
After treatment, the jet-lag nanoparticles could remarkably reduce the level of LA in
TME by limiting the efflux of lactic acid. In addition, the pericytes coverage increased
to 69%, which was significantly higher than that of the mono APA group (47%). Moreover, the results of in vivo pharmacodynamic studies showed that after the synergistic
reconstruction of TME and tumor vascular normalization, the therapeutic effect of
PD-1 monoclonal antibody was three times higher than that of the mono group [152].
To better enhance the infiltration of CTLs in the immune-excluded tumor, Huang
et al. proposed a permeation stimulating strategy based on a dual mechanism that could
synergistically break through the physical barriers of the tumor stroma and strengthen the
recruitment signals to lymphocytes [153]. This strategy includes the administration of
α-mangiferin, a natural xanthone that can relieve liver fibrosis without significant hepatotoxicity, and a DNA plasmid expressing LIGHT (tumor necrosis factor superfamily
14, TNFSF14, CD258), a pleiotropic inflammatory cytokine that can normalize defect
intratumoral vasculatures and stimulate the secretion of chemokines (CCL21 and
CXCL13) facilitating T cell recruitment and activation. To achieve the simultaneous
delivery of the two regulators, as well as the synergistic improvement of CTLs
265Stromal modulation strategies
266 Kai Shi
intratumoral infiltration, calcium phosphate liposomes were constructed and modified
with the targeting peptide (FHK, FHKHKSPALSPV) which specifically binds to
ECM glycoprotein (TN-C) in PDAC stroma. The treatment of nanoparticles reversed
aberrantly activated CAFs and attenuated stromal collagen deposition in PDAC, as
manifested by the decreased expression of α-SMA, FAP, and fibronectin within the
tumor. Notably, high endothelial venous (HEVs) were found in those tumors receiving
the treatments, which express peripheral node addressin and facilitate lymphocyte trafficking into the secondary lymphoid organs. Moreover, the treatment resulted in significantly upregulated chemokines of CCL21 and CXCL13 as well as elevated indexes of
+
CD8
T/CD4+T and CD4+T/Tregs. Accordingly, a further combination of combo
nanoparticles with α-PD-1 exhibited an enhanced tumor suppression than α-PD-1 single
therapy (Fig. 4).
3.2 Targeting tumor extracellular matrix
The abnormally dense ECM contributes to the inefficient penetration of the immunomodulatory nanoparticles [154]. It is known that TME-associated ECM serves as a guiding scaffold for tumor cell proliferation, migration, invasion, and angiogenesis.
As the major structural component of ECM, collagen can pave the migration trajectory for tumor cells to establish migration trajectories for tumor cells, and hyaluronic acid
(HA) helps to increase interstitial fluid pressure (IFP) and impede the diffusion and penetration of nanoparticles [155]. To this end, remodeling of tumor stroma via targeting
ECM by immunomodulatory nanoparticles is put forward for consideration.
3.2.1 Collagen as a therapeutic target to remodel ECM
(1) Inhibiting of collagen synthesis
As the major structural component of ECM, excessive secretion and deposition
of collagen predominantly contribute to the fibrosis of tumor tissues. The dense collagen network in the tumor stroma significantly abbreviates the permeability and
efficacy of nanotherapeutics. It is generally believed that the activation of the
SMAD-2/3 intracellular pathway via TGF-β ligand is heavily implicated in fibrosis,
in which TGF-β1 is considered to be a major driver of fibrotic pathology [156]. The
blockade of TGF-β improved the recruitment and migration of perivascular cells
toward tumor vasculature, as well as the fraction of perfused vessels. In addition, normalization of the neoplastic ECM was achieved by reducing the content of type
I collagen, which allowing enhanced penetration of both conventional chemotherapeutics and nanotherapeutics into tumor stroma.
The angiotensin II receptor antagonists such as losartan have been proved to
inhibit collagen I synthesis and improve the distribution and efficacy of nanotherapeutics in tumors [157]. The antifibrotic effect of losartan is partly attributed
to its antagonism to the angiotensin II type I receptor (AGTR1), which leads to the
FHK-pLIGHT@CaMP
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(Nano-sapper)
Obstacles
reduction
CTLs infiltration
enhancement
+
267Stromal modulation strategies
Before
Recruiting
signals
Stimulation
Enhanced response
of a-PD-1 against PDAC
After
Endothelial cell Collagen Tumor cell Activated fibroblast
CD8+ T cell CD4+ T cell
FHK-LIGHT@CaMP
(Nano-sapper)
α-PD-1
Treg
Apoptotic tumor cell
B cell
Secreted LIGHT CCL21 CXCL13
Quiescent fibroblast
Macrophage
Fig. 4 The schematic dual-mechanism-based CTLs infiltration enhancement initiated by calcium phosphate liposome for synergism with immune-checkpoint inhibitor. The stromal modulation strategy to
improve immunotherapy response in PDAC involves the attenuation of ECM barriers and normalization of intratumoral vasculatures, as well as in situ stimulating the lymphocyte-recruiting chemokines
expression (CCL21 and CXCL13). Reproduced with permission from and produced by Huang Y, Chen Y,
Zhou S, Chen L, Wang J, Pei Y, Xu M, Feng J, Jiang T, Liang K, Liu S, Song Q, Jiang G, Gu X, Zhang Q, Gao X,
Chen J. Dual-mechanism based CTLs infiltration enhancement initiated by nano-sapper potentiates immunotherapy against immune-excluded tumors. Nat Commun 2020;11(1):622.
down-regulation of a positive regulators of TGF-β1 such as thrombospondin-1
(TSP-1) and thereby the suppression of TGF-β1 levels. It was found that intraperitoneal administration of losartan led to a dose-dependent reduction in stromal
collagen in desmoplastic models of melanoma and sarcoma in mice. Moreover, it
also improved the intratumoral distribution and therapeutic efficacy of both
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