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239Challenges and opportunities of nanotechnology in cancer immunotherapy
CHAPTER EIGHT
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Stromal modulation strategies
to improve immunotherapy response
in cancer
Kai Shi
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, China
Contents
1. Background 241
2. Tumor stroma mediated immunosuppression 245
2.1 Tumor vascular endothelial cells 245
2.2 Extracellular matrix 248
2.3 Cancer-associated fibroblasts 252
3. Stromal modulation strategies with nanotechnology to improve immunotherapy 262
3.1 Targeting tumor neovascularization 263
3.2 Targeting tumor extracellular matrix 266
3.3 Targeting cancer-associated fibroblasts 272
4. Conclusions 280
Acknowledgments 281
References 281
1. Background
As one of the most perplexing diseases in human beings, cancer is still lacks effective
methods to be completely cured so far. According to statistics from the World Health
Organization, cancer has become the second leading cause of death globally, accounting
for an estimated 9.6 million deaths in 2018 [1]. The traditional treatment of malignant
tumors has undergone the development of surgical resection, radiotherapy, and chemotherapy, which have shown positive curative impacts on early tumors but less efficacy for
advanced tumors and metastases. Moreover, the limitations of severe nonspecific side
effects, easy to trigger multiple drug resistance and high risk of recurrence make these
traditional methods for cancer treatment urgently need to be upgraded. In recent years,
molecular targeted therapy represented by tyrosine kinase inhibition (TKI) has made
Engineering Technologies and Clinical Translation Copyright © 2022 Elsevier Inc.
All rights reserved.https://doi.org/10.1016/B978-0-323-90949-5.00008-5
241
242 Kai Shi
breakthroughs in antitumor treatment due to its specific killing effects on tumor cells,
which has greatly increased the survival rate of cancer patients. For example, the application of imatinib has enabled patients with gastrointestinal stromal sarcoma (GIST), a
tumor that is highly resistant to radiotherapy and chemotherapy, to obtain a high remission rate of 68% and a clinical benefit rate of 84% [2]. However, it is critical to the people
who are expected to get definite therapeutic benefits and still leads to the inevitable
occurrence of drug resistance, which is attributed to the establishment of compensatory
signaling pathways in tumor cells upon their long-term exposure to TKI [3]. Encouragingly, with the deepening of research in the fields of oncology and molecular immunology, cancer immunotherapy has been widely concerned and has emerged as the most
promising alternative to conventional cancer treatment [4].
The immunotherapy for cancer began with the report of Coley in 1891, who
found that the injection of streptococcus and staphylococcus aureus toxins into
patients could cause tumor shrinkage, which was conside red to be caused by inducing
an antitumor immune response [5]. The milestone work led by Old and Clarke in the
1950s sho wed that Bacillus Calmette–Guerin (BCG), a living attenuated strain of
Mycobacterium Bovis, was able to initiate an inhibitory effect on the tumor in animal
models, whi ch laid the foundation for subsequent tumor immunotherapy [6] .With
the proposal and successive discovery of tumor antigens, t he resea rch on the inter action between the immune system and tumors was promoted, and the "central rul e" in
the field of tumor immunotherapy was established, that is, CD8
+
T cells can selec-
tively kill tumor cells that express specific antigens [7, 8]. In the late 1980s, with
the development and application of in vitro cell culture technology, adoptive therapy
has made substantial progress in the clinic, which is implemented by activation and
amplification of immune effector cells including cytotoxic T lymphocytes (CTL),
cytokine-induced killer cells (CIK), lymphokine-activated killer cells (LAK) and
NK cells are activated and expanded in vitro, and followed transfusion back into
the patient, resulting in the killing of tumor cells directly in vivo [9]. Nevertheless,
some challenging issues such as cumbersome operat ion, difficulty in cell acquisition,
lack of specificity for tumor antigens, and safety considerations, have hindered its wide
application in clinical practice.
Owing to deepening research addressing tumor molecular biology, a new technique
based on the modification of T cell antigen receptor has emerged to improve the tumor
specificity of adoptive T lymphocytes, namely chimeric antigen receptor T cell immunotherapy (CAR-T), which is capable of identifying tumor cells in the nonrestrictive
manner of the major histocompatibility complex (MHC). It is obtained by constructing
a specific chimeric antigen receptor and then expressing it on T lymphocytes through
gene transduction, so as to specifically recognize the target antigen and kill the tumor
cells after the adoptive transfusion. Since it was first proposed in 1989, CAR-T therapy
has made breakthroughs in the treatment of hematological tumors, such as attaining a
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remission rate of 60%–80% in patients with acute lymphoblastic leukemia, which is
far superior to that of conventional chemotherapy [10, 11]. Nevertheless, CAR-T continues to face huge challenges in the treatment of solid tumors, primarily due to the
inability of T cells to effectively infiltrate tumor tissues, anergy induced by immunosuppressive tumor microenvironment (TME), as well as the cytokine storm produced caused
by their excessive immune-stimulation [12].
In addition to the adoptive reinfusion of tumor antigen-specific T cells to enhance the
immune response toward tumors, encouraging progress has been made in the use of
immune checkpoint inhibitors (ICIs) for tumor immunotherapy, which allows restoration of effector functions in the exhausted CD8
+
T cells by blocking the coinhibitory
signal transduction within them, accordingly rescuing their dominated antitumor
immune response [13]. Currently, monoclonal antibodies (mAbs) against coinhibitory
receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death
receptor-1 (PD-1) and its ligand (PD-L1) have been approved for the treatment of
advanced melanoma, small cell lung cancer and metastatic bladder cancer [14]. Moreover, there are also other ICIs that have entered various stages of clinical trials, including
lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin-3 (TIM-3), T cell
immunoglobulin and ITIM domain protein (TIGIT), V-domain immunoglobulincontaining suppressor of T cell activation (VISTA), etc. [15, 16]. Due to the high heterogeneity of tumors, ICIs have only shown a high response rate of 40%–80% in typical
Hodgkin’s lymphoma, melanoma, Merkel cell carcinoma and tumors with high microsatellite instability (MSI-H). However, for solid tumors such as nonsmall cell lung cancer,
head and neck cancer, hepatocarcinoma and urothelial carcinoma, only 10%–35% of the
patients can get rid of the high response rate and benefit from monotherapy [17]. Immunosuppressive and heterogeneous tumor stroma plays an important role in it, which
confines the effective penetration of macromolecular mAbs into tumor tissues, and consequently allows them only to relieve the immunosuppressive effect of T cells located at
the edge of the tumor stroma [18]. Besides, systemic administration of ICIs will inevitably
lead to an immune-related adverse events (irAEs), meaning that they are off-target effects
of an excessively activated immune system [19].
Alongside, therapeutic tumor vaccines have emerged as a pivotal breakthrough in
treating solid tumors since they can induce T cells to attack tumors with high specificity.
The only epoch-making cancer vaccine product currently approved by the FDA is Provenge, adapted to the solid tumor of prostate cancer [20]. The therapeutic principle of
this methodology works on the basis of introducing tumor-specific antigens (TSAs) or
tumor-associated antigens (TAAs) into dendritic cells (DCs), which are subsequently
presented to tumor-specific T lymphocytes, thereby activating them and stimulating
an effective immune response of tumor killing [21]. To date, DCs-based therapeutic
243Stromal modulation strategies
244 Kai Shi
tumor vaccines have undergone phase III clinical trials in malignant melanoma, prostate
cancer, nonsmall cell lung cancer and prostate cancer; nevertheless, the majority of their
therapeutic effects are quite limited (<5%) [22]. The immunosuppressive TME plays a
pivotal role in the ineffective immune response of antitumor vaccines, inhibiting not only
antigen uptake and presentation but also the activation and infiltration of T lymphocytes
by DCs in vivo.
Inviewofthefactthatmostofthetarget molecules of DCs based vaccines a re
derived from TAAs, which are expressed on both tumor cells and other related cells
of the body itself, thereby leading to immune tolerance and autoimmune response
inevitably. Accordingly, the discovery and i dentification of neoantigens specifically
expressed by tumor cells d ue to gene mutations have always been a huge challenge
that limits the successful clinical development of tumor vaccines. With the development and breakthrough of bioinformatics and next-generation sequencing technology,
personalized tumor vaccines that target tumor-specific mutant neoantigens are
attracting great attention. A recent phase I clinical study has revealed that the individualized mutanome vaccines against multiple predicted mutant neo-epitopes stimulate
the immune response of CD8
+
/CD4+T cells and allow the neoantigen-specific killing
of autologous tumor cells in patients with melanoma, resulting in a sustained
progression-free survival [23, 24]. Nevertheless, the extremely complex and costly
preparation process of this individualized therapy has challenged its wide application
in clinical practice.
In general, provided that a positive response to immunotherapy is dependent on
immunomodulatory interactions between tumor cells and their surrounding stroma,
a comprehensive elucidation of the immunomodulatory mechanisms of the tumor
stroma is expected to provide a new methodology for improving the effectiveness
of current immunotherapy. The tumor stroma is an intricate environment, wherein
tumors are dependent on a variety of ext racellular matrices (ECM) and stromal cells,
which include mesenchymal-derived fibroblasts, immune cells and vascular endothelial
cells [25]. The tumor stroma provides support for cells in the matrix, in addition to
secreting different kinds o f cytokines and chemokines, constituting a bridge of information exchange between the stromal and tumor cells. During tumor growth, the
tumor stroma interacts with tumor cells by means of different kinds of immune cells
(for instance, T lymphocytes, dendritic cells, macrophages, and myeloid-derived suppressor cells) to mediate their immune tolerance, accordingly impacting the clinical
effect of immunotherapy. That is w hy blocking the immunosuppression in the
TME benefits recovery and reconstruction of the normal antitumor immune defense
potential of the human body, accordingly enhancing the comprehensive therapeutic
effect of different types of tumor treatment methodologies, which include immunotherapy [26] (Fig. 1).
245Stromal modulation strategies
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Fig. 1 The cellular composition of tumor stroma. The tumor stroma is mainly composed of fibroblasts
(F), extracellular matrix (ECM), and blood vessels (BV) inner lined with endothelial cells (E) and peripheral pericytes (P). More than providing a physical scaffolding support for cancer cells (blue), tumor
stroma serves as a source of various paracrine growth factors (GFs) and cytokines to modulate the
recruitment and infiltration of immune cells including T cells (T), granulocytes (G) and macrophages
(M) within it. Reproduced with permission from Kammertoens T, Sch€uler T, Blankenstein T. Immunother-
apy: target the stroma to hit the tumor. Trends Mol Med 2005;11(5):225–231, copyright © 2005 Elsevier Ltd.
2. Tumor stroma mediated immunosuppression
2.1 Tumor vascular endothelial cells
Tumor vascular endothelial cells originate from normal ones around the tumor, which
functional characteristics and cellular phenotypes have undergone significant changes due
to the long-term exposure to TME, especially changes in certain immunological characteristics, such as reduced expression of adhesion molecules, weakened leukocyte adhesion, poor antigen presentation and secretion of a large amount of ECM. As the first
barrier against the entry of immune cells and immunotherapeutic drugs into tumor
tissues, tumor vascular endothelium not only provides nutrients for tumor growth and
246 Kai Shi
progression, but also helps tumor cells evade immune system surveillance and resist
immune killing.
2.1.1 Secretion of immunosuppressive factors
Some secretory functions of vascular endothelial cells in tumor stroma are changed due to
the induction of tumor cells, which facilitates tumor cell growth, metastasis and immune
escape. Endothelial cells are induced by tumor cells to secrete a variety of immunosuppressive factors to inhibit the function of the immune system, including VEGF, PGE2,
TGF-β, IL-6 and IL-10 [27]. Among them, VEGF with higher secretion level can prevent DC precursors from differentiating into mature antigen-presenting DCs with antigen presentation ability, result in the generation of immature DCs (iDCs) [28].Asan
endothelial cell-specific mitogen and an angiogenesis inducer, VEGF can also induce
the apoptosis of CD8
+
T cells, recruit regulatory T cells (Tregs) and myeloid-derived
suppressor cells (MDSCs) into the tumor focus to form an immunosuppressive microenvironment, thereby attenuating the surveillance and killing of the immune system to
tumor cells. Inhibition of VEGF or its receptor may contribute to the inhibition of tumor
by immune system [29, 30]. In addition, vascular endothelium cells will down-regulate
the expression of adhesion molecules such as ICAM1/2 and VCAM1 on their surface
upon priming with VEGF-A, which leads to concealing of vascular structure and impediment of the adhesion and infiltration of CTLs to tumor endothelium [31]. Voron et al.
reported that VEGF-A derived from tumor microenvironment could induce Tregs proliferation in a VEGFR2 dependent manner, thereby enhancing the expression of PD-1
and other inhibitory receptors involved in CD8
+
T cell exhaustion such as Tim-3,
CTLA-4, and Lag-3, thus promoting immune escape [32]. Combining antiangiogenic
agents targeting the VEGF-A/VEGFR2 axis could synergize with immune checkpoint
blockade for the VEGF-expressing tumors, which are resistant to anti-PD-1 treatment.
2.1.2 The imperfect antigen presentation function
The major histocompatibility complex (MHC) molecules on the cell surface are necessary for T cell-mediated immune responses. Compared with MHC class I molecules
(HLA-I) that are widely expressed on normal vascular endothelial cells, the expression
of MHC-II is site-specific and traditionally found only on the professional antigenpresenting cells such as DCs, mononuclear phagocytes thymic epithelial cells, and
B cells. Upon the stimulation of certain cytokines. MHC-II is critical for antigen presentation to CD4
+
T lymphocytes, which is a subset of immune helper cells responsible for
maintaining antigen-induced lymphocyte proliferation and regulate the body’s immune
response [33]. It is known that the expression of MHC molecules on tumor cells suffers a
diminution or loss. Similarly, on tumor vascular endothelial cells that have been infiltrated in the TME for a long time, the expression of MHC-I molecules is also attenuated,
and the expression of MHC-II molecules is lacking [34]. The decline or absence of MHC
molecules makes the antigen presentation function of tumor vascular endothelial cell
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poor, which hinders the recognition and killing effect of MHC restricted cytotoxic
and helper T cells on tumors.
2.1.3 Weakened interactions with immune cells
Upon receiving antigen stimulation, the effector T cells formed after proliferation and
differentiation need to enter the tumor tissue through the barrier of tumor vascular endothelial cells to exert the killing effect. Under normal circumstances, the migration of
lymphocytes to the outside of blood vessels is completed by the interaction of various
cell adhesion molecules expressed on the surface of endothelial cells and corresponding
ligands on the surface of lymphocytes. In this process, it involves selectin-mediated cell
rolling, adhesion molecules-mediated adhesion and deformation, as well as intercellular
gap opening and transendothelial cell crossing caused by the release of matrix
metalloproteinases [35].
It has been proved that one of the main characteristics of tumor vascular endothelial
cells is their attenuated interaction with immune cells [36]. The rolling and adhesion of
leukocytes in tumor blood vessels are significantly reduced no matter in the resting state
or after cytokine stimulation, and which is associated with the decreased or absent expression of adhesion molecules on tumor vascular endothelial cells. The adhesion molecules
involved in this process mainly include the following three types:
(1) Selectins, including endothelial selectin (E-selectin) and platelet selectin (P-selectin),
are a family of glycoproteins with calcium dependent lectin-like domains [37]. They
are constitutively expressed on the activated endothelial cells and function as cell
adhesion molecules (CAM) to recognize and bind sialylated carbohydrates present
on the surface proteins of leukocytes, thereby facilitating their rolling along and
tethering to the vascular endothelium [38].
(2) Adhesion molecules of the immunoglobulin gene superfamily, including intercellular
adhesion molecule-1(ICAM-1), intercellular adhesion molecule-2 (ICAM-2) and
vascular cell adhesion molecule-1(VCAM-1). Among them, ICAM-1 and
ICAM-2 primarily bind to the leukocyte function associated antigen-1 (LFA-1) on
the surface of T cells, which mediates the adhesion of leukocytes to endothelial cells
and their migration across the endothelium. VCAM-1 is predominantly expressed on
activated vascular endothelial cells, which promotes adhesion and transendothelial
migration of leukocytes. Through mediating the extravasation of leukocytes across
vascular endothelium to sites of inflammation, VCAM-1 plays an important role in
the migration of T lymphocytes to tumor stroma [39]. It has been found that the
expression of VCAM-1 suffered suppression in tumor-infiltrating vascular endothelial cells of both melanoma and lung carcinoma, where it was constitutively expressed
in the blood vessels away from the tumor [40]. Even if the endothelial cells were continuously stimulated with proinflammatory cytokines such as TNFα or IL-1α, the
247Stromal modulation strategies
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