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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_151_библиотеки_им_акад_М_И_Перельмана
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Current Clinical Landscape of Immunotherapeutic Approaches in... 329
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LAG-3 Lymphocyte-activation gene 3
mAb Monoclonal antibody
M-CSF Macrophage colony -stimulating factor
MDSC Myeloid-derived suppressor cell
MHC Major histocompatibility complex
MMP Matrix metalloproteinase
mOS Median overall survival
MSLN Mesothelin
MUC-1 Mucin-1
NET Neutrophil extracellular trap
NK Natural killer cell
NKG2D Natural killer group 2D
OS Overall survival
OVT Oncolytic virus therapy
PD-1 Programmed cell death protein 1
PDAC Pancreatic ductal adenocarcinoma
PD-L1 Programmed death-ligand 1
PFS Progression-free survival
PlGF Placental growth factor
PMN Polymorphonuclear
PSCA Prostate stem cell antigen
rhIL-12 Recombinant human IL-12
ROS Reactive oxygen species
STAT3 Signal transducer and activator of transcription 3
TAA Tumor-associated antigen
TAM Tumor-associated macrophage
TAN Tumor-associated neutrophil
T-BET T-box expressed in T cells
TCR T-cell receptor
TGF-β Transforming growth factor-beta
TH1 T helper 1
TH2 T helper 2
TIGIT T-cell immunoglobulin and ITIM domain
TIL Tumor-infiltrating lymphocyte
TIM-3 T-cell immunoglobulin and mucin domain 3
TLR Toll-like receptor
TME Tumor microenvironment
TNF-α Tumor necrosis factor-alpha
TSA Tumor-specific antigen
TSLP Thymic stromal lymphopoietin
VEGF Vascular endothelial growth factor
VISTA V-domain Ig-containing suppressor of T-cell activation
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1 Introduction
With 50,550 estimated deaths in the USA in 2023 (Siegel et al. 2023), pancreatic
cancer primarily consists of pancreatic ductal adenocarcinoma (PDAC), a recalcitrant disease (Hidalgo 2010). Because symptoms are frequently nonspecific,
individuals frequently present at late stages. The present standard of care for
PDAC is standard cytotoxic chemotherapy, which provides just months of overall
survival (OS) benefit (Conroy et al. 2011; Von Hoff et al. 2013).
PDAC carcinogenesis is characterized by the steady accumulation of driver
mutations, which include the oncogene KRAS (Moskaluk et al. 1997) and the
tumor suppressor gene TP53 (DiGiuseppe et al. 1995). These molecular alterations
are accompanied by histological changes corresponding to the various PDAC
development pha ses (Ho et al. 2020). Morphological development begins with
the establishment of precursor lesions recognized as pancreatic intraepithelial neoplasia (PanIN ) (Hruban et al. 2001), which proceed to invasive adenocarcinoma
(Ho et al. 2020). Modifications in the surrounding tissue stroma occur as cancer
progresses. With its immunological, vascular, and connective tissue components,
non-transformed tissue stroma is essential in providing a homeostatic response to
damage. On the other hand, cancer hijacks such physiological reactions to generate a
favorable tumor microenvironment (TME) for its effective development (Foster
et al. 2018; Ho et al. 2020). Indeed, cancer acts like “wounds that never heal,” and
stromal change is the outcome of “abnormal wound repair” (Dvorak 2015).
Immunotherapeutic approaches have the decent ability to elicit robust anti -tumor
immune responses. Immunomodulators, immune checkpoint blockade (ICB), and
adoptive cell transfer therapy, such as chimeric antigen receptor (CAR) T-cell
therapy, can all help with this. Clinical research employing diverse immunotherapeutic approaches to treat patients with various cancers has yielded outstanding
results from 2010 to the present. Cancer cell-specific immune responses elicited by
immunotherapy differ from those stimulated by therapies acting on the tumor. They
can persist long after the treatment has ceased (Khalil et al. 2016; Farhangnia et al.
2022, 2023).
Tumor immunotherapy has established a novel cornerstone in treating a subset of
diverse solid tumors. However, currently, existing immunotherapies in PDAC have
only shown minimal benefit in terms of survival (Pihlak et al. 2018; Riquelme et al.
2018). The low mutational load of PDAC and the densely packed, inaccessible TME
with fibrotic, hypoxic, and immunosuppressive properties can be linked to the tumor
immunological insensitivity to immunotherapies (Huber et al. 2020; Timmer et al.
2021). However, a meta-analysis revealed that targeted immunotherapy in patients
with pancreatic cancer was superior in terms of increasing survival time and improving immune responses (C hen et al. 2017). Furthermore, chemotherapy and surgery in
conjunction with other immunotherapies may function synergistically. Several cytotoxic drugs and adjuvant treatments have been shown to sensitize the TME to
immunotherapeutic agents by triggering immunogenic cell death, altering evasive
immunological processes, and decreasing immune suppression (Geboers et al. 2019;
Galluzzi et al. 2020).
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Immunotherapy is currently one of the arising areas of focus in pancreatic cancer
therapy. This recalcitrant tumor mainly evades immune surveillance through various
ways, including the secretion of immunosuppressive factors such as transforming
growth factor-beta (TGF-β), establishing an immunosuppressive microenvironment
depleted of T lymphocytes, and the expression of the immune checkpoints
programmed death-ligand 1 (PD-L1) and PD-L2 (Kleeff et al. 2007, 2016). Moreover, in pancreatic cancer, ICB to stimulate T-cell activity is being studied (Feig
et al. 2013 ; Soares et al. 2015). The pancreatic cancer microenvironment is notable
for its extensive desmoplasia, lack of effector T lymphocytes, and T helper 2 (TH2)
cell immunophenotype, all of which support cancer cells to e scape immune surveillance. Therefore, monoclonal antibodies (mAbs) directed against programmed cell
death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have limited
success (Kleeff et al. 2016). Immunotherapies such as PD-1 suppression may
benefit a limited percentage of cancer patients (3%) with hypermutation and
microsatellite instability (Le et al. 2015). Inhibiting the tyrosine-protein kinase
BTK is one approach for modulating the TME to induce a T helper 1 (TH1) cell
immunophenotype. Vaccination is being studied to elicit or enhance pre-existing
immune responses using agents such as GVAX (autologous pancreatic cell lines
transfected with granulocyte-macrophage colony-stimulating factor [GM-CSF]) or
CRS207 (live attenuated Listeria monocytogenes-expressing mesothelin [MSLN])
alone or in combination with a mAb directed against CD40 molecule to stimulate
antigen-presenting cells (APCs) (Le et al. 2015). CD47 and CXC chemokine
receptors are two immune-based targets being investigated. T cells expressing
CARs plus oncolytic virus therapy (OVT) are being studied to stimulate inflammation, immunomodulation, and tumor cell lysis (Khaled et al. 2015).
In this chapter, we elaborate on pancreatic cancer immunosuppressive microenvironment and highlight an extensive spectrum of immunotherapies, including OVT,
adoptive cell transfer therapy (i.e., T-cell receptor [TCR]-engineered T cells therapy,
chimeric antigen receptor [CAR] T-cell therapy, CAR natural killer [NK] cell
therapy, and cytokine-induced killer cells), immune checkpoints blockade and
immunomodulators, cancer vaccines, and immunotherapeutic strategies based on
targeting myeloid cells (Fig. 1).
2 Tumor Microenvironment in Pancreatic Cancer
The interplay of tumor cells with their neighboring microenvironment substantially
influences the pathogenesis of solid tumors. PDAC is a classic illustration of the
wide range of potential tumor-stroma dialogues. PDAC is highly resistant to
emerging immunotherapies, which is by an exclusive assembly of diverse immune
cells that creates a highly immunosuppressive environment, accounting for tumor
progression (Huber et al. 2020). In this section, we delineate the role of immune cells
in the TME of pancreatic cancer.
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Fig. 1 Immunotherapeutic approaches in pancreatic cancer treatment. These approaches include
oncolytic virus therapy, adoptive cell transfer therapy, immune checkpoint blockade, cancer
vaccines, and targeting myeloid cell within the tumor microenvironment of pancreatic cancer.
CTLA-4 Cytotoxic T lymphocyte antigen-4. (This figure was created by Biorender.com)
2.1 Macrophages and Myeloid-Derived Suppressor Cells (MDSCs)
Granulocytes, dendritic cells (DCs), monocytes, and macrophages are innate
immune cells of the myeloid lineage that are crucial in identifying cancer cells,
induction of inflammation, and anti-tumor activities. Chronic inflammation is a
facilitator of tumor grow th in many insidious diseases, including pancreatic cancer
(Hamada et al. 2014). Tumor cells also frequently deploy ways to elude immune
monitoring. Furthermore, myeloid cells perform a double function in cancer. On the
one hand, they trigger anti-tumor immune responses but also encourage local
inflammation that leads to long-term and chronic inflammation linked to cancer
(Huber et al. 2020).
2.1.1 Role of Macrophages in TME
There are tissue-resident macrophages that are not descended from blood
monocytes, such as Kupffer cells in the liver, microglia in the brain, and alveolar
macrophages in the lungs. However, the majority of macrophages in healthy and
inflamed tissues differentiate from bone marrow (BM)-derived monocytes in the
peripheral blood circulation (Mantovani et al. 2022). Circulating monocytic cells are
attracted to the TME and develop into tumor-associated macrophages (TAMs) in the
presence of cytokines and chemokines, as well as other stimuli, like hypoxia and
lactic acid at high levels of concentration (Gordon and Taylor 2005; Huber et al.
2020). However, a study demonstrated that a sizeable part of the macrophages in the
pancreas was generated during embryonic development and increased through
in situ proliferation as the tumor developed (Zhu et al. 2017). TAMs exhibit several
functional states known as polarization states. A vast and expanding spectrum of
TAM subpopulations has been identified. They are often categorized as “M1” and
“M2” macrophages. According to a typical description, M1 macrophages produce
pro-inflammatory cytokines that primarily have anti-neoplastic effects, whereas M2
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macrophages release anti-inflammatory signals that might hasten the formation of
tumors (Mosser and Edwards 2008; Biswas and Mantovani 2010; Bolli et al. 2017).
In numerous tumor types, including pancreatic cancer, studies have shown an
inverse relationship between TAM invasion and patient prognosis (Hu et al. 2016;
Di Caro et al. 2016; Mantovani et al. 2017; Zhang et al. 2020a). Diverse research
teams have shown that TAMs drive immunosuppression, angiogenesis, and tumor
development by releasing growth factors such as vascular endothelial growth factor
(VEGF), cytokines, and proteases in mice models of PDAC (Liou et al. 2015;
Griesmann et al. 2017; Nywening et al. 2018; Filippini et al. 2019).
TAMs can reduce the effectiveness of treatment in PDAC significantly. TAMs
affect the cytidine deaminase activity, a crucial enzyme in gemcitabine metabolism,
leading to resistance to treatments based on gemcitabine in PDAC animal models
(Weizman et al. 2014). By preventing monocyte migration to the TME in mice
models of PDAC, CCR2 suppression promotes T-cell infiltration, increased the
effectiveness of radiotherapy and chemotherapy, and reduced metastasis (Mitchem
et al. 2013 ; Sanford et al. 2013; Liou et al. 2015; Kalbasi et al. 2017).
2.1.2 Role of MDSCs in TME
A diverse population of immature myeloid cells known as MDSCs is often split into
two cell types: monocytic (M-MDSC), which are phenotypically and physically
comparable to monocytes, and granulocytic (polymorphonuclear [PMN]-MDSC),
which are equal to neutrophils. The circulation and the microenvironment of human
malignancies include much more MDSCs, and generally, PMN-MDSCs account for
more than 80% of all MDSCs associated with tumors (Gabrilovich 2017; Veglia
et al. 2021 ).
Here, we highlight evidence related to MDSCs in the PDAC microenvironment.
MDSC levels in human PDAC are correl ated with the cancer stage (Diaz-Montero
et al. 2009; Gabitass et al. 2011; Markowitz et al. 2015). A crucial element promoting MDSC recruitment and differentiation, according to findings from genetically
modified mice models, is GM-CSF, which is generated by tumor cells starting in the
early stages of cancer (Bayne et al. 2012; Pylayeva-Gupta et al. 2012). Additionally,
the accumulation of MDSCs and pancreatic carcinogenesis are facilitated by the
receptor for advanced glycation end products (RAGE) (Vernon et al. 2013). Indeed,
during Ras-mediated pancreatic carcinogenesis, RAGE ablation is linked with
decreased splenic MDSC accumulation (Vernon et al. 2013 ). Upregulation of
Yes-associated protein (YAP) or genes associated with MDSC implies poor survival
in PDAC patients. YAP expression levels are substantially associated with an
MDSC gene signature in primary human PDAC (Murakami et al. 2017). In the
PDAC milieu, CD200, a regulator of myeloid cellular function, is upregulated.
Furthermore, MDSCs from patients with PDAC exhibited increased CD200 receptor
expression. MDSC development may be regulated by CD200 expression in the
PDAC microenvironment (Choueiry et al. 2020).
MDSCs govern the inhibition of CD4
+
and CD8+T lymphocyte activity in the
tumor. Also, MDSCs upregulate PD-L1, which in turn, represses T-cell activation
due to the PD-L1/PD-1 interaction (Pinton et al. 2016). Additionally, MDSCs can
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restrict the T-cell activity by encouraging the growth of immune-suppressive regulatory T cells (T
) through the release of TGF-β and interferon-gamma (IFN-γ)in
regs
an interleukin-10 (IL-10)-reliant manner (Huang et al. 2006; Siret et al. 2020). In
PDAC, targeted reduction of MDSCs maximizes intratumoral accumulation of
stimulated CD8
+
T lymphocytes, tumor epithelial cell death, and tumor stromal
remodeling (Stromnes et al. 2014).
MDSCs can potentially downregulate innate anti-tumor immunity through various strategies. In experimental breast and lung tumor models, MDSCs have been
demonstrated to suppress cytotoxicity in NK cells through cell contact-reliant
pathways and accelerate the transformation of macrophages toward an M2 phenotype (Liu et al. 2007; Sinha et al. 2007; Ostrand-Rosenberg et al. 2012; Huber et al.
2020).
2.2 Natural Killer (NK) Cells
NK cells are a discrete subpopulation of innate lymphoid cells with the inherent
capacity to recognize and eradicate cancerous cells. NK cells play a paramount role
in anti-cancer immunity due to their innumerable cytotoxicity strategies and potential to alter the immune response through cytokine production (Laskowski et al.
2022). Cytotoxic NK cells provide a robust immune response through the production
of cytolytic granules and cytotoxic cytokines when they establish immunological
synapses with target cells (Prager and Watzl 2019; Laskowski et al. 2022). Additionally, NK cells can identify Fc of IgG antibodies on targe t cells via their Fcγ
receptor IIIA (FcγRIIIA; also known as CD16), causing the production of cytokines
and antibody-dependent cellular cytotoxicity (ADCC). Furthermore, owing to their
potential to generate various cytokines and chemokines, which affect the activity of
myeloid and lymphoid cell lineages, NK cells have been raised to as “immuneregulatory” cells (Laskowski et al. 2022).
NK cells, a unique immune effector cell found in the innate immune system, are
thought to contribute to tumor immunosurveillance (Malmberg et al. 2017). Both
preclinical and clinical investigations have shown an association between reduced
NK cell activity with augme nted cancer vulnerability and the likelihood of metastasis (Imai et al. 2000; Guerra et al. 2008; López-Soto et al. 2017). Indoleamine
2, 3-dioxygenase (IDO), matrix metalloproteinases (MMPs), TGF-β, and IL-10
have been revealed to be mediators of immune suppression by PDAC. These
mediators minimize tumor cell recognition and killing by NK cells (Huber et al.
2020).
In patients with PDAC, the relative frequency of NK cells in the blood was
favorably linked with survival. However, compared to healthy participants, PDACassociated NK cells have reduced cytotoxicity (Davis et al. 2012). Peripheral NK
cells from patients with PDAC showed decreased expression of NKG2D, NKp46,
and NKp30, which was linked to the stage and histological grade of the patients
(Husain et al. 2013; Peng et al. 2014). Additionally, the reduced expression of CD96
and CD226 (regulators of NK cell function) on NK cells was associated with cancer
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development in PDAC patients (Peng et al. 2016). Moreover, immune evasion of
NK cells in human pancreatic cancer is associated with Igγ-1 chain C region
(IGHG1) expression. Mechanistically, IGHG1 dampened the cytotoxic activity of
NK cells by inhibiting ADCC (Li et al. 2011). Furthermore, NK cell immune escape
in patients with pancreat ic cancer is associated with impaired localization arising
from lacking CXCR2 and impaired tumor cytotoxicity (Lim et al. 2019).
2.3 Neutrophils
Neutrophils serve as the body’s initial line of defense against infection and react to a
wide variety of pro-inflammatory signals, one of which is cancer. Neutrophils have
flexibility or plasticity, enabling them to modify their function in response to various
inflammatory stimuli (Giese et al. 2019). Due to the inflammatory condition of the
TME in PDAC, tumor cells release pro-inflammatory mediators such as tumor
necrosis factor-alpha (TNF-α) and IL-12 that induce PMNs recruitment to the
tumor site. To drive monocytes and DCs to the TME, PMNs release various
chemokines, including CCL2, CCL3, CCL19, and CCL20 (Xiang et al. 2020).
Furthermore, neutrophils are attracted to factors secreted by tumor cells. IL-1,
CD200, the CXC family (CXCL1, CXCL2, CXCL5, and CXCL8), growth factors
(GM-CSF, granulocyte colony-stimulating factor [G-CSF], and macrophage colonystimulating factor [M-CSF]), and others may be released by tumor cells to attract
neutrophils (Jin et al. 2021).
Neutrophils in the TME have a variety of roles and have been categorized in
myriad ways, such as N1/N2 neutrophils, tumor-associated neutr ophils (TANs),
and PMN-MDSCs (Giese et al. 2019). Depending on their polarization states,
neutrophils may either contribute to the progression of cancers or suppress this
growth. By producing react ive oxygen species (ROS) and reactive nitrogen species,
anti-tumor neutrophils can directly destroy tumor cells. They can also stimulate the
activation of T cells and attract macrophages with an M1 inflammatory profile.
Protumor neutrophils, conversely, can secrete MMP-9, an enzyme that encourages
the development of new blood vessel s and the spread of tumor cells. They can also
inhibit the function of NK cells. Besides, they can recruit anti-inflammatory
macrophages (M2) and T
inhibited by suppressor neutrophils, also known as PMN-MDSCs, along with other
types of pro-tumor neutrophils (Giese et al. 2019).
It is assumed that the neutrophil polarization affects their function in the TME. A
high neutrophil-to-lymphocyte ratio in solid tumors has been found to be linked to a
poor prognosis in patients (Shen et al. 2014). However, these findings do not clarify
whether neutrophils are directly involved in cancer development or are associated
only with advanced disease. There is a broad range of how neutrophil infiltration
affects cancer growth in mouse cancer models (Giese et al. 2019). The distinction
between pro-tumorigenic and anti-tumorigenic neutrophils, designated N1 and N2,
was initially proposed by Fridlender and colleagues. They demonstrated that the
immunosuppressive cytokine TGF-β polarized neutrophils to a pro-tumorigenic
. Furthermore, the activity of CD8+T cells may be
regs
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phenotype (N2) and neutrophil depletion brought about a modest reduction in tumor
development in mice models. SM16 (a TGF-β receptor inhibitor) caused TGF-β
blockage, which increased neutrophils with an anti-tumorigenic phenotype
(N1) (Fridlender et al. 2009).
Neutrophil extracellular traps (NETs) that neutrophils produce are another way in
which they distinguish apart from other immune cells. These include DNA fibers and
proteolytic enzymes secreted by neutrophils to combat invading infections. However, new research indicated that NETs may play a role in the spread of cancer.
DNase I, a NET inhi bitor, was investigated in a mouse model of spontaneous PDAC
and shown to reduce liver metastasis (Zhang et al. 2017). In the PDAC environment,
IL-17 is responsible for recruiting neutrophils and triggers NETosis (Zhang et al.
2020b).
Neutrophils play a part in metastasis because of their ability to move via the
circulatory system and into the tissue. Neutrophils can accompany tumor cells as
they migrate through the circulation. These tumor cells are often circulating tumor
cells that have spread from the central tumor location (Huber et al. 2020; Zhang et al.
2020b). During the process of extravasation and following infiltration into metastatic
locations, neutrophils experience apoptosis and NETosis. This causes their cargo
molecules to be released, which in turn makes a milieu more favorable to tumor
growth. This includes the release of ARG-1 to make an environment that suppresses
the immune system; MMP-9 to stimulate the infiltration of cancerous cells and
angiogenesis; and other potent serine proteases, such as neutrophil elastase,
Cathepsin G, and human proteinase 3. Lipocalin-2, heparanase, CD11 and CD18,
and S100/A9 are other proteins released by neutrophils. For illustration, neutrophils
may stimulate tumor cells by phosphorylating PI3K /Akt after the release of
lipocalin-2. This results in the downstream production of VEGF and hypoxiainducible factor-1 (HIF-1), which are proteins that are essential for the growth of
tumors, vasculature, and chemoresistance (Tao et al. 2016; Huber et al. 2020 ).
2.4 T Lymphocytes
Tumors from patients with PDAC show a wide range of immunological diversity,
with infiltrating T-cell densities and T-cell subpopulation composition (Leung et al.
2012; Bailey et al. 2016a, b; Carstens et al. 2017; Balli et al. 2017; Stromnes et al.
2017;Lietal.2018). Recent research suggests that desmoplastic components may
not impact T-cell accumulation, demonstrating a distinct spatial distribution of
T cells in PDAC (Balli et al. 2017), challenging the notion that the immunosuppressive milieu of fibroblasts and desmoplastic stroma inhib its T-cell infiltration
(Ene-Obong et al. 2013; Balachandran et al. 2017). An improvement in patients’
survival is linked to an increment in the number of CD8
(CTL) that surround cancer cells (Balli et al. 2017). Tumor samples from patients
with long-term survival showed a higher percentage of CD8
T
and a lower percentage of CD4+T cells compared to tumor samples from
regs
patients with short-term survival (Carstens et al. 2017). Longer patients’ survival
+
cytotoxic T lymphocytes
+
T cells, CTLs, and
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was substantially linked with a higher ratio of M1 to M2 macrophages and a higher
number of tumor-infiltrating CD4
T
(Feig et al. 2013).
regs
+
and CD8+T cells, and lesser tumor-infiltrating
2.4.1 T Helper (TH) Cells: TH1, TH2, and TH17
TH1 cells, which express the T-box expressed in T cells (T-BET; or T-Box transcription factor 21 [TBX21]) transcription factor and produce IFN-γ, are a subset of
+
CD4
T cells. By the synthesis of cytotoxic molecules and the secretion of the
cytokine IFN-γ, TH1 cells enhance cellular type I immunity, which includes the
priming, stimulation, and recruitment of CTLs, M1 macrophages, and NK cells, and
facilitates protection against intracellular infections and malignancies. Differentiated
TH2 cells, which are effective against helminths and contribute to allergies and
asthma, are defined by GATA binding protein 3 (GATA3) transcription factor, and
they secrete interleukin IL-4, IL-5, and IL-13. TH1 differentiation is inhibited by
TH2, and vice versa (Huber et al. 2020).
In pancreatic cancer, GATA3
+
T-BET
TH1 cell infiltration, and a higher ratio of GATA3+/T-BET+tumor-
+
TH2 cell infiltration is more prevalent than
infiltrating lymphocytes (TILs) is related with disease development (Tassi et al.
2008; De Monte et al. 2011; Dobrzanski 2013). Patients with PDAC who have a
greater TH2 cytokine profile in their blood have a worse OS rate (Piro et al. 2017;
Galon and Bruni 2020). Human pancreatic cancer cell proliferation was boosted by
the TH2 marker cytokine IL-4, which also increased the signal transducer and
activator of transcription 3 (STAT3), AKT, and mitogen-activated protein kinase
(MAPK) pathway activity (Piro et al. 2017).
DCs expressing the receptor for thymic stromal lymphopoietin (TSLP) were
responsible for the activation and enrichment of TH2 cells in the TME. IL-1 α/β
cytokines released by cancer cells and TAMs trigger the secretion of TSLP by
cancer-associated fibroblasts (CAFs) (Huber et al. 2020). The presence of IL-4expressing basophils corresponds with an elevated TH2/TH1 ratio in tumors and
poor patients’ survival, suggesting that these cells likely contribute to the stability of
the TH2 phenotype in PDAC patients (Brunetto et al. 2019). Furthermore, in patients
with pancreatic cancer, TH2-induced inflammation is associated with worse survival
when basophils are recruited into lymph nodes that drain the tumor (De Monte et al.
2016). In light of the fact that toll-like receptor 4 (TLR4) ligation may increase
pancreatic inflammation, thus, TLR4 activation might underlie the development of
pancreatic cancer. A study revealed that DCs elicit pancreatic antigen-specific CD4
TH2 cells and enhance the progression from pancreatitis to cancer, and MyD88
inhibition is responsible for these effects (Ochi et al. 2012). Additionally, PDACrelated immunosuppression is mediated by Bruton tyrosine kinase (BTK) signaling.
An empirical study demonstrated that macrophages were reprogrammed toward a
TH1 phenotype, which boosted CTLs-induced cytotoxicity, and PDAC development was inhibited in mice treated with the BTK inhibitor ibrutinib or by PI3K
inhibition. Also, TH2-type macrophage programming through BTK activation in a
PI3K-dependent manner is essential for PDAC formation via cross-talk between B
lymphocytes and FcγR
+
TAMs (Gunderson et al. 2016).
+
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TH17 cells contribute to PDAC control. Protec ting against extracellular bacterial
and fungal infections is a primary role of TH17 cells, which rely on the transcription
factor retineic-acid-receptor-related orphan nuclear receptor gamma (ROR γt) to
synthesize IL-17, IL-21, and IL-22 (Gnerlich et al. 2010; He et al. 2011; Mucciolo
et al. 2021). A study indicated that pancreatic tumors had greater TH17 frequencies
than the surrounding normal tissues, and more TH17 cells were present in advanced
(stage III-IV) tumors than in early (stage I–II) tumors. A correlation was also
reported between the number of IL-17
+
T cells present in tumor tissue and the
likelihood of both OS and metastasis. Lastly, the severity of pancreatic cancer was
linked to an increment of systemic IL-17 levels in PDAC patients compared to
control (He et al. 2011). IL-17 promotes the development of pancreatic cancer by
acting via the inflammatory pathway of REG3-JAK2-STAT3 (Loncle et al. 2015). In
response to KRAS and inflammation, the pancreas undergoes a drastic change in
terms of an influx of IL-17
+
T lymphocytes. In addition, overexpression of IL-17A
hastens the onset and development of pancreatic intraepithelial neoplasia
(McAllister et al. 2014). Moreover, pancreatic cancer cells developed tuft cells and
stem cell characteristics in response to IL-17, which was accompanied by
upregulated expression of DCLK1, POU2F3, ALDH1A1, and IL-17RC, genes
involved in cell proliferation and differentiation (Zhang et al. 2018). Hi gh numbers
+
of CD4
TILs generating TNF-α and IL-17 were related to the aggressive disease in
human PDAC (Alam et al. 2015 ).
2.4.2 Regulatory T Cells (T
CD4+T
express a key transcription factor, the forkhead box P3 (FOXP3). The
regs
regs
)
peripheral tolerance, the prevention of autoimmune disorders, and the limitation of
chronic inflammatory diseases are all dependent on T
Patients with pancreatic cancer have a higher frequency of T
(Vignali et al. 2008).
regs
in their peripheral
regs
blood and TME (Liyanage et al. 2002; Lytle et al. 2019). As pancreatic ductal
carcinoma has progressed from the premalignant to the cancerous stage, T
a role in regulating the immune response to it. High levels of T
a worse prognosis in PDAC (Hiraoka et al. 2006). T
and immunogenicity in pancreatic cancer. Also, reducing T
immunity in pancreatic cancer in a CD8
+
-activated T-cell-dependent manner (Jang
can limit DC proliferation
regs
are associated with
regs
stimulates anti-tumor
regs
regs
have
et al. 2017). Contrary to these findings, pancreatic carcinogenesis is hastened by the
depletion of T
suppressive RORγt
the pathogenesis of PDAC may be a result of FOXP3
(Zhang et al. 2020c). Furthermore, pro-inflammatory and immuno-
regs
+
FOXP3+T
proliferate in human pancreatic cancer. Indeed,
regs
+
RORγt+T
function, which
regs
acts as a double-edged sword characterized by pro-inflammatory and immunosuppressive activities (Chellappa et al. 2016).
2.4.3 Cytotoxic T Lymphocytes (CTLs)
CTLs generating IFN-γ, TNF, perforin, and granzymes are the main players in
fighting against cancerous cells. They generate long-lasting memory cells, which
provide immunity against cancer cells in the future (Barry and Bleackley 2002;
Raskov et al. 2021). Better survival in pancreatic cancer is linked to an increment in
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