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The Tumor Microenvironment in Pancreatic Cancer and Challenges to Immunotherapy 389
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Macrophages are primarily recruited to the tumor site and differentiated into
TAMs through various signaling molecules and tumor-secreted factors such as
GM-CSF and IL-6. Also, hypoxia in the TME, together with an acidic and inflamed
environment at the tumor site, recruits monocytes from the bloodstream to the tumor
site and stimulates the differentiation of macrophages to TAMs.
In PDAC, TAMs are one of the dominating immune cell subtypes in the TME.
High infiltration of TAMs in the TME is associated with worse prognosis and more
aggressive disease. The TAMs in the TME of PDAC secrete immunosuppressive
cytokines such as IL-10 and TGF-β, stimulating the infiltration of Tregs while
inhibiting the activity of cytotoxic immune cells. TAMs also modulate the tumor
stroma through the secretion of matrix proteins and proteases such as MMPs,
including MMP9 which promote invasion of the basement membrane (Yang et al.
2021). Furthermore, TAMs have been found to induce resistance to gemcitabine in
PDAC (Liu et al. 2020).
However, the role of TAMs in relation to chemotherapy resistance is not fully
understood.
The various mechanisms by which TAMs influence cancer progression in PDAC
are of great research interest, and the development of future treatment modalities
targeting the differentiation of macrophages to TAMs is especially relevant. Figure 2
summarizes the main immune cells in the TME of PDAC discussed in this section.
3.2 Immune Checkpoints
Immune cells may be able to recognize cancer cells but unavailable to eliminate
them due to various factors in the TME. Likewise, activation and proliferation of
immune cells may be affected by different signaling mechanisms. Cancer cells can
Immune cells of the TME
+
TILs
CD8
Elimination of cancer cells.
Immune stimulatory
signals and recruitment of
other TILs.
MDSCs
Promotion of cancer
stem cell s and
suppression of
cytotoxic responses.
TAMs NK cells
Stimulate the motility,
invasion and intra-
vasation of can cer cells.
Promote angiogenesis
and suppress immune
response s
Fig. 2 An overview and short summary of the main immune cells found in the tumor microenvironment of pancreatic ductal adenocarcinomas as described in this section. TILs tumor-infiltrating
lymphocytes, MDSCs myeloid-derived suppressor cells, TAMs tumor-associated macrophages,
Tregs regulatory T cells, NK cells natural killer cells
Tregs
Highly involved in
immune evasion.
Secretes TGF-β and
influences the composition of the TME
Involved in the
elimination of cancer
cells and activated
rapidly. Often suppressed in the TME
390 A. Orhan
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take advantage of natural checkpoints in the immune system by increasing the
expression of PD-L1 on their cell surface, thereby avoiding immune recognition
and destruction (Akinleye and Rasool 2019).
3.2.1 PD-1 and PD-L1
Antibodies targeting either PD-1 (pembrolizumab and nivolumab) or PD-L1
(atezolizumab and durvalumab) have been developed to inhibit the natural binding
between PD-1 and PD-L1, consequently activating the body’s immune responses
against cancer cells that highly express PD-L1 on their cell surface. The effectiveness of ICIs is found to be dependent on the expression of PD-L1 of cancer cells and
T cells (Davis and Patel 2019). Thus, the level of PD-L1, together with TMB, has
become an important predictor of response to immunotherapy, specifically ICI
therapy.
In PDAC, the cancer cells are found to express PD-L1 on their cell surface.
However, the expression of PD-L1 is minimal in comparison with the membranous
PD-L1 expres sion in other cancer types (Zheng 2017; Lee and Ruppin 2019; Wang
et al. 2020b). High expression of PD-L1 in PDAC has been associated with poor
prognosis (Nomi et al. 2007). The efficacy of ICIs in the treatment of PDAC is
limited to primarily mismatch repair-deficient (dMMR) pancreatic tumors, which
accounts for approximately 1–3% of all pancreatic cancers (Hu et al. 2018). In
PDAC with proficient mismatch repair (pMMR), the efficacy of immunotherapy is
low (Pu et al. 2019). It is hypothesized that the minim al expression of PD-L, together
with other factors related to the TME, causes the previously observed and described
ineffectiveness of ICIs in PDAC (Pu et al. 2019; Eso and Seno 2020). Also, the
infiltration of TILs also influences the tumor response to immune-enhancing
therapies (Lee and Ruppin 2019). The correlation between the abundance of cytotoxic CD8
PDACs have been classified as tumors of low CD8
+
T cells and responsiveness to ICIs has previously been described, and
+
TILs density and thus with a
considerably lower objective response rate to PD-1/PD-L1 inhibitors (Lee and
Ruppin 2019).
The expression of PD-L1 on malignant cells can be activated by inflammatory
cytokines, especi ally through interferon gamma (IFNγ). T cells, including CD4
T helper cells and CD8+cytotoxic T cells, as well as macrophages and NK cells, can
secrete IFNγ. IFNγ can stimulate the differentiation of Th1 cells to CD4
+
T helper
cells which in turn secrete IFNγ, thereby creating a positive feedback loop (Castro
et al. 2018). As previously described, the secretion of IFNγ can enhance the
expression of membranous PD-L1 in cancer cells. This interaction between
T cells, IFNγ, and PD-L1 emphasizes that the presence and degree of PD-L1
expression on malignant cells are influenced by TILs, which generally are sparsely
presented in PDAC (Mucileanu et al. 2021). Thus, the inflammatory signals triggering high PD-L1 expression on cancer cells may be lacking in PDAC due to a low
infiltration of T cells.
+
The Tumor Microenvironment in Pancreatic Cancer and Challenges to Immunotherapy 391
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3.3 Stroma and Fibrotic Tissue
3.3.1 Cancer-Associated Fibroblasts (CAFs)
CAFs are mesenchymal cells of the TME involved in remodeling the extracellular
matrix and promoting tumorigenesis. CAFs can stimulate angiogenesi s, suppress
immune cells involved in the elimination of malignant cells, and enhance the
motility, invasion, and metastasis of cancer cells. In the tumor stroma, CAFs are
the most predominant cell type and play a crucial role in the epithelial-mesenchymal
transition (EMT) of cancer cells. However, some findings suggest that CAFs ha ve a
dual role in cancer and that CAFs initially function as tumor-suppressive cells but
later gain tumor-promoting features (Bhowmick et al. 2004). CAFs can secrete IL-6
and TGF-β promoting immunos uppression. In return, CAFs are activated by TGF-β,
and IL-1 produced by malignant cells and other stromal cells such as macrophages.
Thus, the stimulation and activation of CAFs initiates a positive feedback loop,
making CAFs self-sustaining.
A subset of CAFs are called the myofibroblast CAFs (mCAFs). mCAFs are
involved in the development of fibrotic tissue in the tumor stroma and suppression
of antitumor immunity (Costa et al. 2018). Moreover, heterogeneity of CAFs has
been described in PDAC. The heterogeneity in CAFs is based on the difference in
cell surface markers as well as cytokine production and cell signaling (Ligorio et al.
2019).
In PDAC, the CAFs are responsible for the high density of fibrosis and
desmoplasia surrounding the tumor. The high density of desmoplasia is a major
challenge in the treatment of PDAC, as it affects both the ability to resect tumor
surgically and the delivery of antineoplastic drugs medically. CAFs are often
localized in a closed or open ring, surrounding the tumor almost as a capsule. The
stiffness of CAFs as well as CAFs’ ability to invade the tumor stroma is found to
influenced by TGF-β levels in the TME (Stylianou et al. 2018). The dense fibrotic
stroma due to the high number of CAFs in the TME of PDAC challenges both the
infiltration and efficacy of cytotoxic immune cells but also the penetration of
antineoplastic drugs. Thus, these features of the TME constitute a major obstacle
in the applicability of immune-enhancing treatments for pancreatic cancer and
should be further examined. Targeting CAFs in the TME parallel to standard
oncological treatment could be a promising lead in future treatment strategies for
PDAC. Figure 3 illustrates the typical composition of the TME in PDAC.
3.4 Upregulated Signaling Pathways
3.4.1 SMAD4 and TGF-b
Mothers against decapentaplegic homolog 4 or SMAD4 is a protein involved in the
transforming growth factor beta (TGF-β) signaling pathway (Ahmed et al. 2017).
The SMAD4 protein can form complexes with other SMAD proteins and accumulate in the cell nucleus. In complexes with other SMAD proteins, the SMAD4
protein can bind to the DNA in the cell nucleus through a specific Smad-binding
element (Hahn et al. 1996; Ahmed et al. 2017).
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Tumor
Neo-angiogenesis
Growth factors
Collagen
CAFs
mCAFs
TGF-β
Fig. 3 Visual presentation of the main stromal components of the tumor microenvironment (TME)
contributing to a dense fibrous stroma characterizing pancreatic ductal adenocarcinomas. Growth
factors and signaling molecules such as TGF-β maintain an immunosuppressive TME, while CAFs
initiate tissue remodeling. TAMs can promote angiogenesis and suppress cancer immunity. CAFs
cancer-associated fibroblasts, TAMs tumor-associated macrophages, mCAFs myeloid cancerassociated fibroblasts
TAMs
Normally, the protein serves both as a transcription factor and as a tumor
suppressor through its ability to inhibit cell proliferation and cell growth as well as
reducing the formation of new blood vessels (neo-angiogenesis). The TGF-β/
SMAD4 signa ling pathway normally facilitates cell cycle arrest and apoptosis.
However, mutations of the TGF-β transduction result in the loss of SMAD4 signaling, thereby causing a depletion of the tumor-suppressive properties of the TGF-β/
SMAD4 signaling pathway (Ahmed et al. 2017). Paradoxically, this transformation
of the TGF-β/SMAD4 signaling pathway provides the TGF-β protein tumorpromoting features. Overexpression of TGF-β is associated with increased activation
of the PI3K/AKT and Ras/ERK pathways highly involved in carcinogenesis.
Mutation in the SMAD4 gene is found in more than half of the PDAC cases,
explaining why the SMAD4 protein is also called “deleted in pancreatic carcinoma
locus 4” protein (Hahn et al. 1996). Together with mutations in the KRAS, TP53,
p16, and CDKN2A genes, mutations in the SMAD4 gene are considered the main
drivers of the development and progression of PDAC (Hahn et al. 1996; Tascilar
et al. 2001). Studies suggest that SMAD4 mutations alone do not facilitate the initial
formation of cancer, including PDAC, but rather stimulate the progression of cancer.
Thus, the SMAD4 gene is considered an important driver gene in PDAC (Ottenhof
et al. 2012; Oshima et al. 2013). Loss of SMAD4 expression in patients with PDAC
was correlated with worse prognosis (Xing et al. 2016). Likewise, slightly improved
The Tumor Microenvironment in Pancreatic Cancer and Challenges to Immunotherapy 393
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survival was observed in patients with PDAC and intact expression of SMAD4
(Oshima et al. 2013; Xing et al. 2016).
The TGF-β signaling pathway plays a central role in tumorigenesis.
Overexpression of TGF-β, and overactivation of the signa ling pathway, is associated
with immunosuppression through recruitment of FoxP3
as well as suppression of CD8
+
cytotoxic T cells and natural killer (NK) cells (Batlle
+
regulatory T cells (Tregs)
and Massagué 2019). Likewise, the signaling pathway is involved in the facilitation
of neo-angiogenesis through inducement of vascular endothelial growth factor
(VEGF) and connective tissue growth factor (CTGF) (Padua and Massagué 2008).
TGF-β also facilitates epithelial-mesenchymal transition (EMT) of cancer cells,
allowing invasiveness and increasing their metastatic potential (Derynck and
Akhurst 2007). In addition, TGF-β stimulates the formation of fibrosis by increasing
the release of collagen, fibronectin, and elastin. Fibrosis in relation to a tumor, or
desmoplasia, is one of the major challenges in PDAC (Whatcott et al. 2012;
Karamitopoulou 2019).
In patients with PDAC, the TGF-β levels in blood plasma or serum have been
correlated with survival outcomes (Javle et al. 2014; Gough et al. 2021). Higher
levels of TGF-β in serum are associated with worse prognosis. It is hypothesized that
high TGF-β levels in patients with PDAC may cause an increase in the metastatic
potential of the malignant cells, thereby negatively affecting survival measures. In
continuation, evidence suggest that higher levels of TGF-β increase cellular invasion
and metastasis in the TME of PDAC. It has been described that TGF-β expression is
associated with advanced disease in PDAC (Zhao et al. 2016).
3.5 Driver Mutations
3.5.1 KRAS
The rat sarcoma virus (RAS) prote ins belong to the group of small GTPases and are
involved in cellular signal transduction. The RAS proteins are normally able to
activate genes related to cellular growth and anti-apoptosis. RAS proteins can
activate the mitogen-activated protein kinase (MAP-K) and the PI3K/AKT/mTOR
pathways, which are pathways both involved in cell growth and cell survival
(Malumbres and Barbacid 2003).
Mutations in the RAS genes can lead to overactive signaling of the RAS proteins,
causing uncontrollable cell differentiation, growth, and inhibition of apoptosis
(Malumbres and Barbacid 2003). Approximately 90–95% of all PDACs have
mutations in the KRAS gene (Waters and Der 2018; Buscail et al. 2020). In
mouse models, KRAS mutation coupled with mutations in the TP53 or SMAD4 or
CDKN2A genes accelerates the development of PanINs to progressive metastatic
PDAC (Waters and Der 2018). The higher occurrence of mutations in the KRAS
gene in PDAC compared to other cancer types is not fully understood but may be
related to environmental factors and exposure to carcinogens that may particularly
trigger KRAS mutations.
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The presence of KRAS mutations in patients with PDAC is a negative prognostic
factor. Patients with KRAS-mutated PDAC have poorer prognosis independent
of previous surgical treatment (Bournet et al. 2016). Some subty pes of KRAS
mutations are also found to have a more aggressive phenotype in terms of reduced
overall survival. For instance, KRAS G12D and/or G12R mutations have been
correlated with worse survival outcomes in patients with PDAC (Bournet et al.
2016). The high frequency of KRAS mutations in PDAC has led to the speculation
that targeting cancer-associated KRAS or KRAS downstream signaling pathways
may be novel treatment strategies for PDAC. However, no promising results have
been reported or led to the approval of KRAS inhibitors for the treatment of PDAC
yet. The therapeutic potential of new treatments inhibiting KRAS signaling must be
further investigated.
3.6 Neoantigens and Hypermutability
3.6.1 Tumor Mutational Burden
Tumor mutational burden (TMB) is a term used to quantify the number of mutations
per megabase in malignant cells of a tumor. High TMB has previously been
associated with potential response to immunotherapy. Some cancer types are
found to have higher values of TMB, whereas other cancer types have less. There
is both a variation in the mean TMB value in different cancers and between patients
with the same cancer type. This heterogeneity can be useful when selecting which
patients may benefit most from immune-enhancing treatment modalities. Also,
treatments that may provoke higher TMB in malignant cells prior to immunotherapy
could be a strategy in a personalized approach to cancer therapy in the future.
Assessment of TMB is thus relevant and a research subject of interest that still
need further examination.
In general, the TMB is low while the expression of neoantigens is sparse in
PDAC. A meta-analysis found that high TMB was present in approximately 1.1% of
all included subjects (Lawlor et al. 2021). The PDAC samples that harbored high
TMB values were also found to contain mutations of the MMR proteins, suggesting
a correlation between MMR deficiency and high TMB. In continuation, the best
responses to immunotherapy in PDAC have been described in the high TMB and/or
MMR-deficient subtypes. The rareness of both high TMB values and MMR deficiency in PDAC composes a major challenge in the use of immunotherapy as a
treatment for disease.
3.6.2 Mismatch Repair Proteins
The MMR proteins are enzymes involved in genome stability that detect and repair
errors during the DNA replication and recombination. The MMR proteins repair
single-base pair mismatches as well as smaller insertions and deletions. Also, the
The Tumor Microenvironment in Pancreatic Cancer and Challenges to Immunotherapy 395
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proteins are responsible for repairing some types of minor DNA damage, thereby
defending the cells from harmful changes in the genome (Li et al. 2020).
Cells with deficient MMR proteins (dMMR) or microsatellite instability (MSI)
have considerably higher occurrences of DNA mutations. Deficiency of the MMR
proteins can be due to germ line mono- or biallelic mutations in the MMR encoding
genes, often seen in syndromes such as Lynch syndrome. However, dMMR is also
seen in sporadic tumors in somatic cells, typically due to promoter hypermethyl ation
of the MLH1 gene.
Deficiency in the MMR proteins is associated with elevated presence of mutationassociated neoantigens in solid cancers (Wu et al. 2021). Mutation-associated
neoantigens can be recognized by immune cells, leading to higher infiltration of
lymphocytes. A higher number of infiltrating immune cells at the tumor site,
especially CD8
+
T cells, may ultimately improve prognosis and enhance a patient’s
likelihood of response to PD-1/PD-L1 inhibitors (Wu et al. 2021). In CRC, dMMR
was associated with improved disease-free survival (DFS) and overall survival (OS),
presumably due to the increase of immune infiltration in dMMR tumors as a result of
elevated mutation-associated neoantigens. It is hypothesized that the observed
positive effect on prognosis is related to the immune system’s increased awareness
and reaction to malignant cells (Wu et al. 2021).
In sporadic PDAC, deficiency in the MMR proteins is rare, accounting for
approximately 1–3% of all cases (Laghi et al. 2012; Abrha et al. 2020; Ghidini
et al. 2020). The MMR status of PDACs can assist in the prognostication and choice
of therapy. Some studies have reported better prognosis in patients with dMMR
PDAC compared to patients with proficient MMR proteins (pMMR) (Brahmer et al.
2012; Patnaik et al. 2015; Ghidini et al. 2020).
However, the relation between MMR status and survival outcomes in patients
with PDAC is still uncertain and should be further investigated. The number of
patients with dMMR in sporadic PDAC should also be evaluated in greater cohorts
to determine a more precise occurrence of dMMR status in sporadic PDAC.
4 Conclusion
PDAC is a fatal disease with a low 5-year survival rate and increasing incidence
worldwide. Despite the recent advances in the treatment of cancer, the potential
treatments of PDAC are few. The composition of TME represents a major challenge
in the treatment of PDAC. The TME of PDAC is dominated by immunosuppressive
signals and a dense fibrous stroma, challenging the standard surgical and medical
treatment approaches to cancer. Thus, a more multidimensional approach, targeting
the different components of the TME that contribute to disease progression, may be
needed to optimize responses to standard treatment modalities and to improve
survival measures.
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