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Current Clinical Landscape of Immunotherapeutic Approaches in... 379
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The Tumor Microenvironment in Pancreatic
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Cancer and Challenges to Immunotherapy
Adile Orhan
Abstract
Pancreatic ductal adenocarcinomas (PDACs) contribute to around 7% of all
cancer-related deaths worldwide with a 5-year survival rate less than 10%. The
incidence of the disease is rising, while the treatment modalities are few for
especially the late stages of PDAC. Despite advances in the field of immuno-
oncology, the treatment of PDAC with immunotherapy has not yet shown
promising results. The composition of the tumor microenvironment (TME)
contributes to the aggressive disease phenotype and treatment resistance. In this
chapter, the different components of the TME in PDAC will be described and
discussed to further elucidate some of the major challenges of the TME in relation
to immunotherapy.
Keywords
Immunohistochemistry · Immuno-oncology · Immunotherapy ·
Neo-angiogenesis · Pancreatic ductal adenocarcinoma · Tumor
microenvironment · Tumor-infiltrating lymphocytes
A. Orhan (✉)
Center for Surgical Science (CSS), Department of Surgery, Zealand University Hospital, Koege,
Denmark
Department of Clinical Oncology, Zealand University Hospital, Roskilde, Denmark
e-mail: aor@regionsjaelland.dk
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2022_65
Published online: 19 November 2022
381
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1 Introduction
1.1 Immunotherapy
Treatments that enhance the immune system against cancer cells are named immunotherapy. Immune checkpoint inhibitors (ICIs), which inhibit the natural survival
signals between immune cells and normal cells, are the best-known type of immunotherapy. Examples of immune checkpoint inhibitors are pembrolizumab and
nivolumab that targets the programmed cell death protein 1 (PD-1) on lymphocytes
or ipilimumab that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
During the past decade, ICIs in the treatment of malignant melanoma, NSCLC, and
renal cell carcinomas have significantly improved patient survival (Motzer et al.
2015, 2018, 2019; Ott et al. 2019a, b; Rini et al. 2019; Hamid et al. 2019; Tykodi
2014). However, the potential role of immunotherapy as an effective treatment for
other types of solid cancers, such as pancreatic cancer, is still uncertain, and the
clinical studies are still ongoing.
The effectiveness of immunotherapy is influenced by many factors, including the
characteristics of both the cancer cells and the surrounding TME (Wang et al. 2017;
Giuliano et al. 2018; Karamitopoulou 2019; Galon and Bruni 2020). For instance,
the expression of programmed death-ligand 1 (PD-L1) on cancer cells and the tumor
mutational burden (TMB) are found to influence the likeliness of response to
immunotherapy, specifically ICIs (Lee and Ruppin 2019; Davis and Patel 2019b).
On the other hand, the tumor fibrotic tissue (stroma) surrounding the cancer cells as
well as the density of tumor-infiltrating lymphocytes (TILs) and neo-angiogenesis in
the TME have been found to impact both prognosis and treatment response to
immunotherapy (Galon and Bruni 2019).
1.2 Pancreatic Cancer
Pancreatic cancer is recognized as one of the most lethal cancers with a relative
5-year survival less than 10% (Jemal et al. 2017; Saad et al. 2018). The disease
contributes to around 7% of all cancer-related deaths worldwide, and the incidence
of the disease has been rising since 1990.
A newly published research letter in JAMA based on data from the Surveillance
Epidemiology and End Results (SEER) database found the sex-specific trends for
pancreatic cancer in the United States (USA) among different age groups to be
significantly increasing in both women and men (Gaddam et al. 2021). Interestingly,
the incidence in younger individuals is estimated to be mostly increasing. With the
trends described in the paper, the number of patients with pancreatic cancer is
expected to be dominated by women younger than 55 years in following years.
Another study found that pancreatic cancer is expected to become the second leadi ng
cause of cancer-related death in the USA in 2030 (Rahib et al. 2014). The existing
data and statistics on pancreatic cancer are thus alarming, emphasizing the need for
research on the matter to establish better diagnosis and improved treatment of the
disease.
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The composition of the tumor microenvironment (TME) is recognized to be one of
the main therapeutic difficulties in pancreatic ductal adenocarcinomas (PDACs). The
TME in PDAC is often dominated by immunosuppressive cells and a dense network of
desmoplastic tissue (Karamitopoulou 2019). Furthermore, neo-angiogenesis, leaky
blood vessels, and early formation of micrometastases contribute to the rapid prog ression
of the disease (Khan et al. 2015; Shi et al. 2016).
Escaping anticancer immunity, inducing angiogenesis, promoting inflammation,
and dissemination are all important factors among the well-establish hallmarks of
cancer (Hanahan and Weinberg 2011; Hanahan 2022). Identifying pathways that
promote progression in PDAC may assist in identifying novel targets and development of treatment approac hes. Characterizing the immunosuppressive signature of
PDAC may specifically contribute with novel insight to how the immune system can
be recruited against cancer cells. Also, examining the characteristics of the TME
including the interaction between immune cells, stromal components, and
neo-angiogenesis may help ease the understanding of the complex nature of the
disease and how it can be targeted in a multidimensional manner. In this chapter, the
constitution of the TME in PDAC as well as the major difficulties in applying
immune-enhancing treatment modalities for PDAC will be discussed.
2 Immune Signatures of Tumors
2.1 Hot, Cold, Immunosuppressed and Excluded Tumors
Some solid cancer types, such as malignant melanoma and lung cancer, are
characterized as more likely to respond to immunotherapy. In general, such tumors
have been found to have a high degree of T cell infiltration, especially that of
cytotoxic CD8
+
T cells in the TME. Likewise, tumors that respond efficiently to
immunotherapy exhibit a high expression of PD-L1 on immune cells and a greater
number of neoantigen and greater tumor mutational burden (TMB) (Galon and Bruni
2019, 2020). On the other hand, some cancers, including pancreatic cancer, are less
likely to show significant clinical benefit from immunotherapy. Generally, such
tumors have sparse infiltration of T cells, small number of neoantigens, and low
mutational burden. The variations in the density of T cell infiltration, checkpoint
activation, and degree of mutational burden assist in the categorization of solid
cancers in different groups according to their immune signature (Galon and Bruni
2019). This categorization may help predict the possible clinical benefit of immune-
enhancing treatments.
Galon and Bruni have previously addressed some of the main challenges to
immunotherapy. In their paper from 2019, the authors describe that tumors with a
microenvironment dominated by CD8
+
lymphocytes especially intratumorally are
recognized as immunogenically warm tumors, which distinctively responds better to
immunotherapy (van der Woude et al. 2017; Galon and Bruni 2019). On the other
hand, tumors with low CD8
+
cytotoxic T cells that are excluded from the tumor
region respond less to immune-enhancing treatments and are thus classified as
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immunogenically cold tumors. However, the authors also discuss two more
subtypes of immune signatures in tumors according to the level and localization
of CD8
+
T cell in the TME. The two additional subtypes are (1) the alteredimmunosuppressed tumors and (2) the altered-excluded tumors. These subtypes
include tumors with immune signatures that cannot be classified under the traditional
hot or cold groups and further emphasize the complexity of the relation between the
TME and the immune system.
The altered-excluded tumors are characterized by a small number of infiltrating
+
CD8
T cells, generally localized to the tumor border, whereas the TME is often
dominated by abnormal vasculature, hypoxia, and a dense stroma. The alteredimmunosuppressed tumors also exhibit a minimal amount of CD8
+
T cell infiltration
in the TME. However, the infiltrative T cells in the altered-immunosuppressed
tumors are mainly localized to periphery of the tumor, whereas the intratumoral
region is primarily dominated by the presence of Tregs and myeloid-derived suppressor cells (MDSCs). Figure 1 illustrates the different immune signatures of
tumors, and Table 1 summarizes the main characteristics of the immune signatures
of tumors.
Tumors classified as altered-immunosuppressed or the altered-excluded tumors
both may respond to immunotherapy to a certain degree. However, the efficacy of
immune-enhancing treatments may be increased when simultaneously targeting
components of the TME that impact the density and localization of infiltrating
cytotoxic T cells.
PDAC is often classifi ed as an immunogenically cold tumor due to the low
mutational burden, low infiltration of lymphocytes, and a TME dominated by
immunosuppressive cells and desmoplastic tissue (Galon and Bruni 2019, 2020;
Infiltrating T cells
Altered-immunosuppressed tumor
Myeloid derived cells
Fig. 1 An overview of some of the main characteristics of the four different immune signature
types exhibited by tumors according to Galon and Bruni
Recruit ment
Regulatory T cell s
T cells in tumor periphery
Altered-excluded tumor
Hypoxia
Dense stroma
Cold tumorHot tumor
Absence of T cells
T cells at tumor border
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Table 1 Summarizes the different immune signatures of tumors according to T cells and TME
characteristics
Tumor immune
signature T cells TME
Hot High abundance of T cells
Cold Absence of infiltrating T cells High number of tumor-associated
Alteredimmunosuppressed
Altered-excluded Number of T cells are small
that are primarily localized
intratumorally
T cells are sparse and mainly
localized to the tumor
periphery
and primarily localized to the
tumor border
Signals recruiting further T cell
infiltration, sparse stromal components,
less to minimal hypoxia
macrophages and cancer-associated
fibroblasts (CAFs)
High number of Tregs and MDSCs
localized more centrally in the tumor.
The TME is dominated by suppressive
signals from immune suppressive cells
Dominated by hypoxia, a dense stroma,
and CAFs. Unsuitable environment for
the survival and efficacy of T cells
Karamitopoulou 2019). Immunogenically cold tumors are less responsive to immunotherapy. Clinical studies have also described the majority of PDACs to be
nonresponsive or less responsive to immunotherapy.
3 The Characteristics of the TME in PDAC
The unique composition of the TME in PDAC is hypothesized to be one of the major
reasons that immunotherapy is less efficient in the treatment of the disease. The TME
in PDAC consists of many different cell types and a complex interplay of signaling
molecules. The main and well-described characteristics of the TME in PDAC will be
discussed in the next sections of this chapter.
The following components of the TME in PDAC will be described and discussed:
• Immune cells and immune checkpoints
• Stroma and fibrotic tissue
• Upregulated signaling pathways
• Driver mutations
• Neoantigens and hypermutability
3.1 Immune Cells
Immune evasion is a well-known hallmark of cancer (Hanahan and Weinberg
2011; Hanahan 2022). Normally, the immune system can detect cancerous
cells and eradicate them. However, when cancer is clinically developed, the
immunosurveillance against malignant cells is insufficient. There are various causes
to why the immune system may not be able to destroy cancerous cells. It can be
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caused by a continuous suppression of immune cells involved in the detection and
killing of malignant cells, as well as it can be caused by an inability of immune cells
to infiltrate the tumor site, activ ate killing mechanisms, or survive and proliferate at
the tumor site. The role of immune cells in cancer development and progression is
apparent, but the interplay between immune cells and cancer cells in the TME is
complex. Some of the main immune cells involved in immunosurveillance in PDAC
will be discussed in the next section.
3.1.1 Tumor-Infiltrating Lymphocytes
Immune cells can identify malignant cells and combat cancer growth (Galon and
Bruni 2020). Immune cells that are especially of importance in cancer are the
lymphocytes. As components of the adaptive immune system, lymphocytes that
be activated through antigen-presenting receptors present on their cell surface
by antigen-presenting cells (APCs) of the innate immune system. Activated
lymphocytes can subsequently recruit additional lymphocytes and other immune
cells to eliminate damaged cells. Thus, an important interaction between the innate
and adaptive immune system exists for proper activation and function of each.
Mature lymphocytes are normally found in the bloodstream and can exit the
blood circu lation to enter sites of damage or danger. Lymphocytes which are found
in and/or around tumor cells are called tumor-infiltrating lymphocytes (TILs). TILs
are involved in the recognition and elimination of can cer cells (Paijens et al. 2020).
The immune cells that are mainly involved in recognizing and killing cancer cells are
the CD3
(Farhood et al. 2019). Along these cells, the CD4
lymphocytes (B cells) are important mediators of the adaptive immune responses
(Galon and Bruni 2020). The FoxP3
+
CD8+T cells (cytotoxic T cells) and the natural killer cells (NK cells)
+
T regulatory cells (Tregs) are also recognized
+
lymphocytes and CD20
as impo rtant mediators of the immune response to tumors, as they suppress the
immune system (Takeuchi and Nishikawa 2016). During the past decade, research
have found that the density of TILs in a tumor predicts patient prognosis as well as
likelihood of treatment response to immunotherapy in different cancers.
Pancreatic tumors are generally poorly infiltrated with T cells and are therefore
often characterized as immunogenically cold tumors that are less responsive to
immune checkpoint inhibitors (ICIs) (Galon and Bruni 2019, 2020). Compared to
other cancer types, the infiltration of T cells in PDAC is sparse. However, a
significant association between the levels of TILs and survival outcomes has been
described in PDAC (Orhan et al. 2020). Especially, high levels of cytotoxic CD8
T cells in the TME have been correlated with significantly improved overall survival,
progression-free survival, disease-free survival, and cancer-specific survival among
patients with PDAC (Orhan et al. 2020). In contrast, high infiltration of FoxP3
T cells was associated with worse prognosis. These findings are consistent with
studies on TILs in other cancer types (Zheng et al. 2018; Lee et al. 2018; Ding et al.
2018; Idos et al. 2020). The localization of TILs is also of importance. As described
previously, the immune signature of a tumor relies not only on the presence of
cytotoxic T cells but also their localization. In PDAC, the localization of immune
+
+
+
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cell infiltration is also found to influence survival. High density of specifically
cytotoxic T cells in the tumor center has been associated with improved prognosis
both in retrospective cohorts and in a large meta-analysis (Zhang et al. 2017; Lohneis
et al. 2017; Orhan et al. 2020). Analyzing the presence, density, and location of TILs
in the TME of PDAC is therefore relevant when estimating patient prognosis.
3.1.2 Natural Killer Cells
Natural killer (NK) cells are a part of the innate immune system and mediate antiviral
as well as antitumor functions. They are cytotoxic and can induce lysis of infected or
damaged cells. Together with CD8
+
T cells, they are highly involved in the destruction of cancerous cells. Thus, NK cells are an important part of the first-line defense
of the immune system and play a central role in tumorigenesis.
Normally, NK cells are activated within just a few hours through the recognition
of damage-associated molecular patterns (DAMPs) and pathogen-associated
patterns (PAMPs). NK cells can kill target cells fast with the release of lytic toxins
and do not need prior antigen sensitization. In comparison, the activation and
differentiation of naïve T cells can take over 1–2 weeks.
In the bloodstream, NK cells can detect and eliminate circulating tumo r cells
(Santos et al. 2014). Normally, circulating tumor cells are destroyed by NK cells
within a short timeframe from first entering the circulation. However, studies have
found that the activity of circulating NK cells decreases as cancer progresses (Leone
et al. 2018). The NK cells are therefore involved in suppressing tumor growth and
progression.
In the TME, the function of NK cells is often suppressed by signals and
molecules, as well as by the extracellular components of the TME such as fibrotic
tissue. Tumor-infiltrating NK cells are of special interest from a therapeutic point of
view, as the density of NK cell infiltration in the TME impacts prognosis (Nersesian
et al. 2021). Increasing the migration, activation, and efficacy of NK cells in the
TME is thus of importance.
In PDAC, the expression of NK cells in the TME has been associated with
survival outcom es (Orhan et al. 2020; Wang et al. 2020a). The TME of PDAC is
characterized by a high number of stromal cells (e.g., cancer-associated fibroblasts
(CAFs), stellate cells, etc.) and fibrotic tissue, as well as high TGF-β levels
(Karamitopoulou 2019). Studies suggest that NK cells are excluded from the TME
of PDAC by interactions between different stromal cells and NK cells (Ene-Obong
et al. 2013). Likewise, high levels of TGF-β are found to impact NK cell activation
and function through IL-6 secretion from CAFs (Huang et al. 2019). Other cytokines
involved in the inhibition of NK cell activity and proliferation are IL-10 and IL-23
which may also be high in the TME of PDAC. The levels of IL-10 induce infiltration
of Tregs that consequently increase further secretion of IL-10. Thus, many of the
dominant components of the TME in PDAC stimulate and maintain an immunosuppressive phenotype. The impairment of the cytotoxic NK cell function in the TME
increases cancer growth, and interventions that can stimulate the migration and
activation of NK cells in the TME of PDAC are therefore highly relevant.
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3.1.3 Myeloid-Derived Suppressor Cells (MDSCs)
Myeloid-derived suppressor cells (MDSCs) originate from stem cells from the
bone marrow and constitute of cells from the myeloid lineage. Under normal
circumstances, these cells are held in check, but during chronic infections or cancer,
the number of MDSCs may expand rapidly. MDSCs are recruited to the bloodstream
and further into the TME with the help of chemo kines. Once in the TME, MDSCs
can expand and suppress cytotoxic responses. A subgroup of MDSCs, the monocytic
MDSCs, may additionally differentiate into tumor-associated macrophages (TAMs)
that contribute to the maintenance of an immunosuppressive TME.
In PDAC, the number of circulating MDSCs in the peripheral blood is correlated
with higher cancer stage, suggesting that MDSCs are recruited as disease progresses.
The differentiation of myeloid progenitor cells in the bone marrow to MDSCs is
found to be influenced by the growth factor and granulocyte-macrophage colonystimulating factor (GM-CSF). Malignant pancreatic epithelial cells are found to
produce GM-CSF (Bayne et al. 2012).
The recruitment of MDSCs from the circulation to the tumor site is found to be
regulated by chemokines and hypoxia. Hypoxia-inducible factors (HIFs) influence
both the recruitment and differentiation of MDSCs in the TME of PDAC. HIFs are
also responsible for the recruitment of Tregs to the TME. Studies indicate that the
differentiation of MDSCs to TAMs of the M2 phenotype is rapidly increased in
hypoxic environments (Kumar et al. 2016). Together with TAMs, MDSCs have also
been found to promote cancer stem cells through the secretion of pro-inflammatory
molecules (Porembka et al. 2012). Thus, MDSCs have been found to play a central
role in cancer progression. Currently ongoing clinical and preclinical studies are
investigating how targeting MDSCs may impact the course of cancer progression.
3.1.4 Tumor-Associated Macrophages (TAMs)
Tumor-associated macrophages are macrophages found in the TME of solid cancers.
TAMs are alternative activated macrophages, thus also called M2 macrophages. M2
macrophages are important for Th2 immune responses including tissue remodeling.
TAMs produce anti-inflammatory cytokines such as IL-10. High infiltration of
TAMs is associated with cancer progression and poor oncological outcomes in
different cancer (Chittezhath et al. 2014). In the TME, TAMs are primarily localized
in the hypoxic areas and are important mediator of angiogenesis (Nasrollahzadeh
et al. 2020). TAMs can stimulate the motility, invasion, and intravasation of cancer
cells through epidermal and vascular growth factors and their ligands as well as by
immunosuppressive cytokines. Through the initiation of prostaglandin synthesis and
production of platelet-derived growth factors, TAMs are found to initiate angiogenesis in the TME as well a s suppressing cytotoxic T cells and NK cells (Sahraei et al.
2019). TAMs are highly involved in constituting and maintaining an immunosup-
pressive TME. High levels of IL-10 and TGF-β produced by TAMs inhibit T cell
proliferation as well as T cell responses involved in cancer cell elimination. Furthermore, IL-10 produced by TAMs increases the tumor infiltration of Tregs and drives a
more aggressive disease phenotype in cancer.
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