Sage Journals: Discover world-class research

Abstract

Pancreatic cancer is one of the most lethal diseases around the world, for hardly detection and poor prognosis. Recent years, functions of the tumor microenvironment and immune cells attract people’s view and there is emerging evidence implicating some immune cells hold the key points in the metabolism, invasion, and metastasis in pancreatic cancer. In this review, we highlight some main immune cells, such as Tumor-associated neutrophils (TANs) and macrophages (TAMs), Pancreatic stellate cells (PSCs), Myeloid-derived suppressor cells (MDSCs), and Regulatory T cells (Tregs). Furthermore, we review current clinical applications and discuss potential values in future.

Keywords

Pancreatic cancer Tumor-associated neutrophils Tumor-associated neutrophils macrophages Pancreatic stellate cells Myeloid-derived suppressor cells and Regulatory T cells (Tregs)

Introduction

Pancreatic cancer (PCa) is a lethal tumor and a major cause of death worldwide. Approximately 45,750 recent PCa deaths have been recently reported in the US alone.¹ PCa is behind only lung cancer and colon cancer in the US in 2018 for cancer-associated deaths. Worldwide, over 400,000 deaths occur annually due to PCa.² The five-year survival rates of PCa are one of the poorest (∼5%).² On account of the lack of effective early detection methods, patients with early symptoms such as upper abdominal discomfort and loss of appetite are often diagnosed with gastric disease, whilst diagnosed PCa patients frequently exhibit local invasion or metastatic tumors, missing the optimal therapeutic window.³ The TNF system for PCa states that T1-T3 tumors are “potentially resectable” and often receive surgery.⁴ However, as low as 15% of patients are deemed suitable for surgical interventions and most die within 2 years.⁵ For advanced and/or metastasis, gemcitabine and erlotinib (EGFR inhibitor) can be efficacious.⁶

Amongst PCa subtypes, pancreatic ductal adenocarcinoma (PDAC) is the most common (≥95% of PCa cases). PDAC arises from the epithelial ducts,⁷ the reasons for which remain obscure. Pancreatic intraepithelial neoplasias (PanINs), mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms are considered origins of PDAC. The majority are thought to develop from PanINs.⁸ An array of genes and signaling pathways have been implicated in the tumorigenesis and progression of PCa, including K‐ras-related proteins, Notch, Hedeghog, Wnt, F‐box proteins, PI3/Akt, and mTOR. Notably, these pathways mediate inflammatory responses.^9–15 Inflammation was discovered as a cancer-causing factor in 1863 by Virchow and has since gained intense interest in the progression of PDAC. Inflammation is critical to tissue protection with a loss of tissue homeostasis known to be carcinogenic.¹⁶ Interestingly, organs with chronic inflammation have a heightened risk of carcinogenesis. For example, patients with inflammatory bowel diseases have a higher risk of colorectal cancer,¹⁷ esophageal cancer is more prevalent in patients with Barrett’s disease,¹⁸ and PCa is associated with chronic pancreatitis.¹⁹

Immune cell populations regulate inflammation,²⁰ and immunotherapy has emerged as a common cancer-targeting strategy. Immuno-regulation can improve the survival rates of PCa patients. In this review, the immune cells regulating carcinogenesis and tumor progression will be discussed, including Tumor-associated neutrophils (TANs) and macrophages (TAMs), Pancreatic stellate cells (PSCs), Myeloid-derived suppressor cells (MDSCs), and Regulatory T cells (T-regs). These cells have been shown be involved in the progress of PDAC; their functions are summarized in Figure 1. We will further discuss the clinical utility of these immune cell populations.

Figure 1.

The interactions between tumor cells and immune cells.

Tumor-associated macrophages

TAMs account for the largest number of invasive monocytes and possess plasticity. A characteristic of PDAC is the abundant invasion of tumor-associated macrophages. In recent years, an array of studies suggest that specific subpopulations of macrophages support tumor progression and macrophages constitute up to 50% of the tumor mass, including tumor infiltration and immune cells in the tumor microenvironment (TME).^21,22 Macrophages participate in tumor progression including early carcinogenesis, development, and metastasis.²³ Of note, M1-TAMs are anti-tumoral in cancer-initiating conditions. Upon the establishment of tumors, macrophages become pro-cancerous and switch to the M2 type.²⁴ Large TAM numbers are frequently associated with poor prognosis.²⁵

Interaction between TAMs and pancreatic cancer cells

In PCa, macrophages assist tumor proliferation, invasion, and metastasis.²⁶ As previously discussed, cancer-related inflammation is a hallmark of cancer. TAMs are involved in tumor progression through the secretion of pro-inflammatory cytokines or chemokines. M2-polarized macrophages suppress adaptive immunity via cytokines such as IL-10 and IL-12 and chemokines such as CCL13 and CCL18.²⁷ In addition, M2-polarized macrophages enhance Th-2 responses through enhanced cytokine secretion; thus, inhibiting the anti-tumor immune responses mediated by T cells.^28,29 PDAC tumors create a hypoxic TME and promote angiogenesis creating a hypoxic and nutrient-deprived environment. During tumor progression, TAMs secrete HIF-1α, a transcription factor for many angiogenesis responsive genes.²⁴ Upon distant tumor cell migration, TAMs release CCL2 that recruits inflammatory monocytes, converting them into metastasis macrophages.³⁰ Of note, malignant cells are cleared by the immune system; however, PCa evades the immune response through the creation of an immunosuppressive niche, a major reason for its poor prognosis. The secretion of IL-10 by the TAMs contributes to immune evasion. TAMs that express CD120a+ and CD120b+ promote T cell apoptosis and anti-tumor responses, enhancing the ability of PDAC to undergo immune evasion.³¹ Chang et al. have reported that ezrin in PDAC-derived small extracellular vesicles can modulate the polarization of macrophages to the M2 phenotype and promote PDAC metastasis, while knockdown of ezrin promoted the M1 phenotype.³² Another report found that exosomal K-Ras protein from tumor cells could be taken up by macrophages resulting in a switch to an M2-TAM phenotype via STAT3-dependent fatty acid oxidation to promote the tumor progression.³³ Zhang et al. found that TAMs could protect cancer cells from complement-dependent cytotoxicity (CDC) by up-regulating CD59 via the IL-6R/STAT3 signaling pathway.³⁴ On the other hand, tumor cells release chemokines that recruit TAMs.

The clinical application of TAMs in the treatment of pancreatic cancer

Regarding clinical applications, Liu et al. found that combined blockade of TGF-β1 and GM-CSF was able to improve chemotherapeutic effects in pancreatic cancer patients by inhibition of M2-polarized TAMs and induction of CD8⁺ T cells.³⁵ Ireland et al. reported that blockade of stromal Gas6 could inhibit pancreatic cancer metastasis.³⁶ Other reports have found that the chemotherapy drug gemcitabine recruited M2-type TAMs into the stroma of PDAC xenografts,³⁷ implying that gemcitabine may be a potential risk factor for refractory PDAC. Osborne et al. reported that a vaccine targeting gastrin, the polyclonal antibody stimulator, when given in combination with an anti-PD-1 antibody, caused less fibrosis, fewer inhibitory Treg lymphocytes, and fewer TAMs in PDAC, and improved patient prognosis.^38,39 In general, immunotherapy has exhibited great potential in cancer treatment, but in pancreatic cancer, the tendency of immunotherapy to cause immunosuppression results in a far from satisfactory outcome. M2-TAMs play an important role in this problem. Li M has found that targeted blockade of PI3K-γ and colony-stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) pathways, which are involved in the infiltration and polarization of M2 TAMs, could remodel the tumor immune microenvironment and activate anti-tumor immune responses.⁴⁰ Zhang et al. have found that IFN-γ could improve the efficacy of PD-1 blockade therapy via blocking the CXCL8-CXCR2 axis.⁴¹ The relevant clinical applications of TAMs in PC are summarized in Table 1.

Table 1.

Relevant clinical application of TAMs in PCs treatment.

Effect observed	Main mechanism of this effect	Potential application in future	Reference
PDAC-derived sEV-EZR promotes the metastasis of cancer	PDAC-derived sEV-EZR could modulate the polarization of macrophages to M2 phenotype	Targeting sEV-EZR can be considered a promising therapeutic strategy to inhibit PDAC metastasis	32
Exosomal KRAS protein promotes the progress of tumor	Exosomal KRAS protein from tumor cells could be taken up by macrophages and causes switch to an M2-TAMs via STAT3-dependent fatty acid oxidation	Extracellular KRAS acts as a key mediator of cancer cell-macrophage communication and a novel anticancer target	116
Higher infiltration of TAMs and higher expression of CD59 predicted worse survival of PC patients	TAMs could protect cancer cells from CDC by up-regulating CD59 via the IL-6R/STAT3 signaling pathway	Multispecific antibodies targeting TAMs, CD59 might be a new promising strategy for cancer immunotherapy	34
Combined blockade of TGF-β1 and GM-CSF improves the chemotherapeutic effects	Combined blockade of TGF-β1 and GM-CSF could inhibit M2-polarized TAM and induction of CD8 positive T cells	TGF-β1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects	35
Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells, and inhibits pancreatic cancer metastasis	Pharmacological blockade of Gas6 signaling partially reverses epithelial-to-mesenchymal transition (EMT) of tumor cells and supports NK cell activation	The rationale for targeting Gas6 in pancreatic cancer and use of NK cells as a potential biomarker for response to anti-Gas6 therapy	36
Gemcitabine treatment of PDAC contributes to tumor progression and therapeutic resistance	Gemcitabine recruits M2-type TAMs into the stroma of pancreatic cancer	Targeting M2-polarized TAMs may benefit PDAC patients at risk to become refractory to current anticancer regimens	(37)
PAS prolongs survival of patients with pancreatic cancer	PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors	PAS combined with PD-1 Ab function as a novel approach to improve treatment strategies for pancreatic cancer	38, 39
CSF-1/CSF-1R pathways were involved in the formation of suppressive TIME	Blockade of PI3k-γ and CSF-1R could reduce M2 TAM level, elevate M1 TAM level, and suppress the infiltration of MDSCs	Inhibition of both PI3K-γ and CSF-1R could remodel TIME and activate anti-tumor immune responses	40
IFN-γ enhances anti-PD1 efficacy in PC	IFN-γ suppresses tumor-derived CXCL8 and inhibits the tumor trafficking of CXCR2CD68 macrophages by blocking the CXCL8-CXCR2 axis	IFN-γ functions as a translatable, therapeutic option to improve the efficacy of PD1 blockade therapy	41

Tumor-associated neutrophils

Neutrophils regulate acute inflammation.⁴² Neutrophils account for ∼60% of all leukocytes in the circulation and are recruited to the sites of infection or inflammation, interacting with an array of immune cells.⁴³ In traditional immunology, neutrophils act in host defenses, immunomodulation, and tissue injury, and patients with neutrophil deficiencies (such as neutropenia) are more susceptible to microbial and fungal infections.⁴⁴ When the inflammatory response occurs, neutrophils are recruited from the peripheral blood to the sites of inflammation. Neutrophils then produce ROS, granular proteins, and cytokines to kill microorganisms and clear infections.⁴⁵ Of note, the neutrophils that originate from myeloid precursors, the primary responsive cell types of the innate immune response,⁴² are involved in tumor progression, malignant transformation, anti-tumoral immunity, and angiogenesis,⁴³ with some studies suggesting that TANs and peripheral neutrophils and granulocytic MDSCs in the bone, spleen, and blood regulate tumor progression.⁴⁶

Interaction between Tumor-associated neutrophils and pancreatic cancer cells

Similar to the TAMs, TANs promote oncogenic (referred to as N2 TANs) and anti-tumor (or N1) phenotypes,^46,47 that differ according to the degree of activation rather than polarization.⁴⁸ In PCa, N1-like and N2-like neutrophils act in the early stages of tumor growth. The proliferation and maturation of neutrophils are dependent on G-CSF and GM-CSF,⁴⁹ which in PCa cells recruit neutrophils to the tumor site.⁵⁰ The presence of increased levels of TANs is often associated with poor clinical outcomes.⁵¹ TANs produce proteases such as PR3, elastase, cathepsin G, and MMP-8 and -9 to enhance PCa cell invasion and migration.⁵² Another report has found that TANs can support circulating tumor cells (CTCs), the precursors of metastasis, in PCa, promoting their survival and extravasation; it is possible that vimentin-positive CTCs may be biomarkers for the diagnosis and treatment of patients with PCa.⁵³ Chao et al. have found that CXCR2 inhibition by genetic ablation prevented neutrophil accumulation in pancreatic tumors and led to a T cell-dependent suppression of tumor growth.⁵⁴

Clinical applications relevant to Tumor-associated neutrophils in pancreatic cancer

Zhang et al. have reported that high expression of CXCL5 was observed in PDAC tumor tissue and was positively correlated with the presence of intratumoral neutrophils, indicating poor patient survival.⁵⁵ It has also been found that neutrophil activation markers including cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase could be used to predict cancer-associated venous thrombosis (VTE) in PDAC.⁵⁶ The neutrophil-to-lymphocyte ratio (NLR) could reflect the cancer-induced systemic inflammation response and be seen as a risk factor for poor long-term prognosis in cancer. The NLR and cancer antigen 199 (CA199) were considered as important diagnostic biomarkers for patients with PC. Qin et al. found that the combination of NLR and CA199 had higher specificity for the diagnosis of pancreatic cancer in patients with type 2 diabetes.⁵⁷ Additional research has found that the CXCLs-CXCR2 axis holds an essential position in the mobilization of neutrophils from the bone marrow to the tumor site.^58–61 Blockade of the CXCLs-CXCR2 axis could result in a decrease in the infiltration of neutrophils and M2-TAMs and delay pancreatic cancer progression.⁶² Wang et al. observed that CD177 was considered to represent neutrophils and was strongly expressed in the stroma and blood vessels around PDAC tissue, indicating that expression of CD177 could be used to represent neutrophil infiltration and the prognosis of PDAC patients.⁶³ The relevant clinical applications of TANs in PC are summarized in Table 2.

Table 2.

Clinical application of TANs in PCs treatment.

Effect observed	Main mechanism of this effect	Potential application in future	Reference
CXCR2 attracts neutrophil into tumors and promotes the progress of cancer	CXCR2-ligand axis helps establish an immunosuppressive microenvironment in PDA	CXCR2 inhibition could prevent TANs accumulation in PCs and led to a T cell-dependent suppression of tumor growth	54
CXCL5 could promote carcinogenesis and cancer progression in PDAC	High CXCL5 expression is positively correlated with poor survival and the increased infiltration of several types of immune suppressive cells	CXCL5 could be a promising therapeutic target for PDAC immunotherapy	55
Seven miRNAs and calprotectin were up- or down-regulated before VTE	Unclear	Plasma miRNAs and neutrophil activation markers could be used to predict VTE in PDAC	56
NLRs and PLR of PC patients with type 2 diabetes were higher than patients with type 2 diabetes alone and healthy subjects	Unclear	Combining PLR and CA199 values could allow earlier diagnosis of PC in type 2 diabetic patients	57
Heterozygous knockout of CXCR2 in PKF mice (PKF2h mice) prolonged survival and inhibited both tumor angiogenesis and PDAC microinvasion	PDAC and CAFs accelerated each other’s invasion and migration through the CXC chemokines-receptor (CXCLs-CXCR2) axis	Blocking of the CXCLs-CXCR2 axis in tumor–stromal interactions could be a therapeutic approach against PDAC progression	62
OS was inversely associated with increased expression of CD177	CD177 was considered to represent neutrophils promoting the progress of tumor	Expression of CD177 has potential prognostic value in PDAC.	63

Pancreatic stellate cells

Pancreatic stellate cells are located in endocrine and exocrine PCa tissues.⁶⁴ In 1982, PSCs were identified in mouse pancreatic ducts and have abundant cytoplasmic lipid droplets and vitamin A levels.⁶⁵ PSCs were also shown to be present in healthy pancreatic samples of rats and humans.⁶⁶ Recently, the PSCs in islets have been termed fibrogenic islet stellate cells,⁶⁷ which have fewer lipid droplets than typical PSCs and are more easily activated by stimulators, to reduce proliferation and migration.⁶⁸ In recent years, PSCs have been shown to regulate extracellular matrix (ECM) turnover through the regulation of matrix-degrading enzymes,⁶⁹ and the ECM causing the fibrosis is primarily formed by PSCs. PSCs can be divided according to two distinct biological phenotypes, namely, quiescent and activated PSCs. Quiescent PSCs express high levels of glial fibrillary acidic protein and desmin and when activated to myofibroblasts, express high levels of α-SMA, and display enhanced collagen I-III, fibronectin, and ECM components, thus promoting pancreatic fibrosis.⁷⁰

The interaction between Pancreatic stellate cells and pancreatic cancer

Jiang J observed that nerve growth factor (NGF) from PSCs could promote the proliferation and invasion of cancer cells by activating the PI3K/AKT/GSK signaling pathway.⁷¹ It has also been found that TGF-β1 secreted by PSCs negatively regulates L1CAM expression through canonical TGF-β-Smad2/3 signaling, promoting the stemness and tumorigenicity of pancreatic cancer cells.⁷² Steins et al. found that the stroma from high-grade PDAC contained both reduced collagen and activated PSCs, identified colony-stimulating factor 1 (CSF-1) as the ligand that deactivated PSCs, and suggested that inhibition of its receptor CSF1R may be a useful therapeutic target.⁷³ Kuntze observed that stimulating Piezo1 activated PSCs by inducing Ca influx, leading to increased cellular motility and ECM traction, suggesting that environmental pH might influence the mechanical output of PSCs and favor the early local invasion of PDAC cells.⁷⁴ Mounting evidence suggests that cancer cells influence PSCs via mitogenic and fibrogenic factors to enhance their activation, proliferation, migration, and ability to remodel the ECM.⁷⁵ During tumor inflammation, TGF-β1, PDGF, IL-1β, IL-6, and TNF-α are released into the PCa TME to stimulate qPSCs.^76,77 PSC activation leads to elevated production and secretion of these molecules.⁷⁸ Proteins secreted from the activated PSCs are also associated with cancer progression and epithelial-to-mesenchymal transition (EMT), known to occur during embryonic development, tissue regeneration, organ fibrosis, and tumor formation.⁷⁹ EMT occurs during the initial stages of pancreatic tissue fibrosis, and activated PSCs enhance the expression of EMT-related genes.⁸⁰ Other studies found that PSCs can inhibit apoptosis, increase tumor invasion, and promote metastasis.⁸¹

The clinical application of Pancreatic stellate cells in the treatment of Pancreatic cancer

Tozzi et al. found that H⁺/K⁺ ATPases were overexpressed in pancreatic cancer and that selective targeting of these enzymes by proton pump inhibitors (PPIs) could reduce the progress of PDAC.⁸² It has also been found that nanoparticles causing antagonism of CXCR4 and down-regulation of miR-210/KRAS were able to inactivate PSCs and promote the action of cytotoxic T cells could improve pancreatic cancer therapy.⁸³ PSCs have been shown to stimulate the migration of cancer cells, and it is possible that silencing SMAD7 in these cells might suppress IL-1R1 expression and reduce the stimulatory effects of IL-1α, resulting in reduced cell migration.⁸⁴ Another report claimed that the hepatocyte growth factor (HGF)/c-MET pathway is up-regulated in PC and mediates the interaction between cancer cells and PSCs, while inhibition of this pathway in combination with gemcitabine could eliminate both metastasis and tumor growth.⁸⁵ Wang K had found that PAK1 inhibitors induced increased numbers of intra-tumoral CD4 and CD8 T cells, attenuation of PSC activation, extending survival in murine PDA models. More importantly, PAK1 inhibitors plus immune checkpoint inhibitors might improve the efficacy of immunotherapy of PDAC.⁸⁶ The relevant clinical applications of PSCs in PC are summarized in Table 3.

Table 3.

Clinical application of PSCs in PCs treatment.

Effect observed	Main mechanism of this effect	Potential application in future	Reference
NGF/TrkA regulated the PC cell proliferation and invasion	TrkA was involved in EMT, and NGF/TrkA could activate PI3K/AKT/GSK signal pathway	NGF/TrkA could be considered as a potential therapeutic target for PC patients	71
TGF-β1 secreted by PSCs enhanced stemness potential and tumorigenicity	TGF-β1 negatively regulated L1CAM expression, through canonical TGF-β-Smad2/3 signalling	Rescuing L1CAM expression had the potential to improve the prognosis of PDAC patients	72
High-grade PDAC reduced collagen deposition	High-grade PDAC features stroma via CSF-1	Targeting CSF1R had the potential to maintain a tumor-restricting microenvironment
TME of PC could promote tumor evolution and contribute to therapeutic resistance	IL1β was driven by TLR4 signaling and NLRP3 orchestrated an immune-modulatory program supporting pancreatic tumorigenesis	Targeting this IL1β/TLR4/NLRP3 might provide an effective PDA therapeutic strategy	73
Cholesterol-modified polymeric CXCR4 antagonist nanoparticles for codelivery of anti-miR-210 and siKRAS could improve the prognosis	The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection	A local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy	77
TGFβ signaling suppressed IL-1α mediated pancreatic stellate cell induced carcinoma cell migration	Depletion of SMAD7 up-regulated the effects of TGFβ and reduced the expression of IL-1R1, promoting carcinoma cell migration	SMAD7 might represent a target for inhibition of IL-1α induced tumor–stroma interactions	84
Triple therapy (Hi + Ci + G) could reduce the tumour size, proliferating cancer cell density and metastasis of PC	The HGF/c-MET pathway was up-regulated in PC and mediated the interaction between cancer cells and PSCs, facilitating PC progression	Targeting HGF/c-MET with relevant inhibitors and cancer cells with chemotherapy completely eliminated metastasis and tumour growth	85
Inhibition of PAK1 stimulated anti-tumor immunity	Inhibition of PAK1 increased intratumoral CD4 and CD8 T cells, and sensitized PDA cells to killing by cytotoxic lymphocytes via down-regulation of PD-L1 expression	PAK1 inhibitors in combination with immune checkpoint inhibitors might result in improved efficacy of immunotherapy of PDA.	86

Myeloid-derived suppressor cells

In the 1990s, extramedullary hematopoiesis (EMH) and neutrophilia were identified during tumor progression, promoting tumor vascularization and immune-evasion. This phenomenon was associated with increased serum hematopoietic, abnormal myeloid cell differentiation and colony-stimulating capacity.⁸⁷ Abnormal myeloid cells were first characterized as natural suppressors (NS) that inhibit CTL activity.⁸⁸ NSs lack membrane markers for mature T cells, B cells, and NK cells, as well as macrophages⁸⁹ and were termed MDSCs with potent immune-regulatory activity.⁹⁰ MDSCs exist as granulocytic or poly-morphonuclear MDSCs (PMN-MDSCs) that are similar to neutrophils and monocytic MDSCs (M-MDSCs) that are similar to monocytes.⁹¹ Recent studies have identified another population of MDSCs that induce colony-forming activity and other myeloid precursors, named early-stage MDSCs.⁹² In general, MSDCs regulate the progression and metastasis of tumors through immunosuppression, TME remodeling, the establishment of a pre-metastatic niche, angiogenesis, cancer cell stemness, and EMT.^93-95

The interaction between Myeloid-derived suppressor cells and pancreatic cancer

There is emerging evidence that PDAC cells can release pro-inflammatory metabolites, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), to favor the expansion and accumulation of MDSCs.^50,96 In addition, Trovato et al. found that high levels of MDSCs were associated with poor patient prognosis and that STAT3 was crucial for monocyte re-programming.⁹⁷ In other research, higher MDSC levels were found in PC compared to healthy controls and premalignancy.⁹⁸ ETS homologous factor (EHF) is a tumor suppressor in PDAC. Liu et al. observed that tumoral EHF deficiency could cause MDSC accumulation while EHF overexpression might improve the PDAC immunotherapy checkpoint.⁷⁰ Obesity is often considered as a risk factor related to the poor prognosis of cancer patients, including PDAC. Turbitt et al. found that adiposity induces MDSC accumulation which might favor an immunosuppressive environment that promotes tumor growth.⁹⁹

The relevant clinical application of Myeloid-derived suppressor cells in pancreatic cancer

As described above, blockade of PI3k-γ and CSF-1R can reduce the M2 TAM level and elevate the M1 TAM level. However, a simultaneous decrease in MDSC infiltration of tumors was also observed.⁴⁰ Neoadjuvant therapy (neoTx) has dramatically improved the prognosis of patients with PDAC. There are reports that neoTx-driven selective depletion of regulatory T cells and MDSCs could improve the prognosis of patients.¹⁰⁰ Zheng et al. had found that icariin, derived from the traditional Chinese medicine Herba Epimedii, was able to inhibit the development of pancreatic cancer by inhibiting M2 TAMs and PMN-MDSCs.¹⁰¹ Qiu et al. reported that the anti-tumor effect of 2-AG also promoted an immunosuppressive microenvironment by increasing the population of MDSCs.¹⁰² Urolithin A (Uro A), a novel natural compound derived from pomegranates, was reported to target PI3K/AKT/mTOR signaling pathways and has the potential to be a novel therapeutic agent for PDAC.¹⁰³ The relevant clinical applications of MDSCs in PC are summarized in Table 4.

Table 4.

Clinical application of MDSCs in PCs treatment.

Effect observed	Main mechanism of this effect	Potential application in future	Reference
Adiposity induced MDSC accumulation to promoting tumor growth	Adiposity induced MDSC accumulation, which might contribute to an immunosuppressive environment promoting tumor growth	Reducing weight might reduce the accumulation of immunosuppressive cell to improve the prognosis of patients	99
NeoTx was not only cytotoxic but also had pleiotropic, beneficial effects on all cellular and noncellular components of pancreatic cancer	Neoadjuvant regimes were able to reverse the immunosuppressive behavior of malignant cells on pancreatic cancer microenvironment	Combinational approaches might unleash long-term and more effective anti-tumor responses and improve prognosis of pancreatic cancer	100
Icariin inhibited the development of mouse pancreatic cancer	Icariin inhibited M2-TAMs and PMN-MDSCs	Icariin could be considered as a potential therapeutic target for PC patients	101
2-AG exhibited direct anti-tumor effects	2-AG inhibited pancreatic cancer proliferation, induced DC phenotypic maturation, and increased population of MDSCs	2-AG could be considered as a potential therapeutic target for PC patients	102
Treatment of PDAC cells with Uro A inhibited the growth of tumor xenografts and increased OS of mouse models	Uro A could decrease phosphorylation of AKT and p70S6K and re-program the tumor microenvironment	Utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway	103

Regulatory T cells

Treg cells are the main mediators of immune homeostasis and are responsible for the regulation of diverse immune responses including autoimmunity, allergies, microbial infections, and cancers.¹⁰⁴ However, their inhibitory activity often antagonizes protective immunity and this may favor disease progression.¹⁰⁵ PDAC is characterized by an immunosuppressive microenvironment which favors the growth of cancer and resistance to therapy. Treg cells undoubtedly play an essential role in this.

The interaction between Treg cells and PC cells

In the context of PDAC, the level of Treg cells is considered a prognostic factor as PC cells can recruit the Tregs at an early stage with the Treg cell count increasing along with the development of cancer.¹⁰⁶ On the other hand, Treg cells depletion can cause attenuation of tumor growth.¹⁰⁷ However, other research reports that the deletion of Treg cells may accelerate PDAC carcinogenesis through increased recruitment of myeloid cells, leading to further immune suppression.¹⁰⁸ Hypoxia has been shown to be an important factor in promoting cancer growth. In PDAC, a hypoxic microenvironment contributes to the recruitment of Tregs and depletion of cytotoxic T cells.

The relevant clinical application of Treg cells in PDAC

In many kinds of cancer, chemotherapy is seen as an effective treatment strategy. Research has shown that chemotherapy can selectively deplete Treg cells to improve patient prognosis.¹⁰⁹ Burks et al. reported that ISG15 pathway knockdown decreases the rate of tumor incidence and improves the survival rate by reversing the proliferation of tumor cells and Tregs.¹¹⁰ Perez-Santos et al. used bispecific antibodies specifically binding to OX40 and CTLA-4, which target Treg cells in the tumor microenvironment, and demonstrated that these anti-OX40/CTLA-4 antibodies had anti-tumor activity against PC.¹¹¹ Treg cells expressing CC chemokine receptor 4 (CCR4) were also found to attenuate the anti-tumor immune responses causing the dismal prognosis of several cancers including PC. A phase I study of the anti-CCR4 antibody, Mogamulizumab, in combination with an anti-programmed death-1 (PD-1) antibody, Nivolumab, showed an acceptable safety profile, anti-tumor activity, and may this be a potentially effective option in PC immunotherapy.¹¹² On the other hand, Huang et al. found that simultaneous administration of oxaliplatin and cationic lipid-assisted nanoparticles could induce synergetic anti-tumor effects by mediating immune responses including reducing the number of Tregs. This therapeutic strategy was shown to be applicable to the treatment of PCs.¹¹³ Similarly, Jing et al. observed that a Stimulator of Interferon Genes (STING) agonist could inhibit the progression of PC by altering the immune microenvironment including decreasing the levels of suppressive Tregs.¹¹⁴ Lennon et al. found that the inhibition of ephrinB2-EphB4 combined with radiation could reduce the numbers of Tregs and this Treg depletion Tregs in combination with radiation reduced both tumor growth and fibrosis.¹¹⁵ In addition, Cheng et al. found that KRAS mutations were associated with Treg levels in serum, and together these predicted a worse prognosis for patients with advanced PDAC.¹⁰⁸ The relevant clinical applications of Tregs in PC are summarized in Table 5.

Table 5.

Clinical application of Tregs in PCs treatment.

Effect observed	Main mechanism of this effect	Potential application in future	Reference
Treg cell ablation could evoke effective anti-tumor immune response	Treg cells engaged in interactions between CD8 T cells and DCs, and restrained their immunogenic function	Therapeutic manipulation of Tregs/T cells/DCs might provide an effective approach for the targeting of PDA.	107
ISG15 pathway knockdown reversed the proliferation and colony formation of PDAC cells	ISG15 knockdown decreased PDL-1 expression and the number of Tregs	Targeting the ISG15 pathway or in combination with immunotherapy might improve survival for patients with PDAC	110
Tregs expressing CCR4 could suppress anti-tumor immune responses	Mogamulizumab would decrease the populations of effector Tregs and increase CD8 T cells	Combining nivolumab with mogamulizumab improved effect of cancer immunotherapy	112
Contemporaneous administration of OXA and CLAN could achieve synergetic anti-tumor effects	Administration of OXA and CLAN could promote dendritic cell maturation, increase tumor-infiltrating T lymphocytes, and decrease the number of Tregs	Administration of OXA and CLAN was applicable for PCs and offered a strong immunological memory effect	111
STING agonist could increase the survival of tumor-bearing mice	STING agonist could change the tumor architecture and alter the immune profile	STING agonist could inhibit the PC progression	114

Conclusion

In conclusion, PCa remains a threat to human health due to difficulties in diagnosis, poor therapeutic effects, and poor prognosis. With improvements in living standards, its incidence is increasing on a yearly basis, and the 5-year survival rates remain less than 5%. In recent years, the treatment of PCa has emphasized the importance of early diagnosis and metastasis control, in which immune regulation plays a key role. This review summarizes recent findings on the immune regulation of PCa and proposes new clinical applications. To date, the immune regulation of PCa is still insufficient, and further clinical assessments are needed. However, immune mechanisms have the unique advantage of assisting early diagnosis, clinical treatment, and predicting prognosis in PCa.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from the National Natural Science Foundation of China (81672402), Provincial Natural Science Foundation of Jiangsu, China (BK20171305), Jiangsu Key R & D Program Social Development Project, China (BE2018689), Research Programs of Jiangsu Provincial Commission of Health and Family Planning, China (H201434), “Six one Project” Research Projects of High-level Medical Personnel of Jiangsu Province (LGY2016054), “Six Talents Peak” High-level Talent Selection and Training Project of Jiangsu Province (2014-WSW-038), Science and Technology Support Program Project of Zhenjiang, China (SH2014024), and Qing Lan Project Funding of Jiangsu Colleges and Universities.

ORCID iD

Min Xu

References

Siegel

Miller

Jemal

. Cancer statistics. CA Cancer J Clin 2019; 69(1): 7–34.

Bray

Ferlay

Soerjomataram

, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394–424.

Zhang

Zeng

Chen

, et al. Pancreatic cancer epidemiology, detection, and management. Gastroenterol Res Pract 2016; 2016: 8962321.

Hidalgo

. Pancreatic cancer. N Engl J Med 2010; 362(17): 1605–1617.

Steele

Karim

Leach

JDG

, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 2016; 29(6): 832–845.

Stathis

Moore

. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 2010; 7(3): 163–172.

Garcea

Dennison

Pattenden

, et al. Survival following curative resection for pancreatic ductal adenocarcinoma. A systematic review of the literature. JOP 2008; 9(2): 99–132.

Murphy

Hart

Lima

, et al. Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. Gastroenterology 2013; 145(5): 1098–1109.e1.

Mann

Ying

Juan

, et al. KRAS-related proteins in pancreatic cancer. Pharmacol Ther 2016; 168: 29–42.

10.

Gao

Long

Wang

. Role of Notch signaling pathway in pancreatic cancer. Am J Cancer Res 2017; 7(2): 173–186.

11.

Schlotman

Xie

. Deciphering the role of hedgehog signaling in pancreatic cancer. J Biomed Res 2016; 30(5): 353–360.

12.

Javadinia

Shahidsales

Fanipakdel

, et al. Therapeutic potential of targeting the Wnt/beta-catenin pathway in the treatment of pancreatic cancer. J Cell Biochem 2018.

13.

Wang

Maitra

Wang

. The emerging roles of F-box proteins in pancreatic tumorigenesis. Semin Cancer Biol 2016; 36: 88–94.

14.

Ebrahimi

Hosseini

Shahidsales

, et al. Targeting the Akt/PI3K signaling pathway as a potential therapeutic strategy for the treatment of pancreatic cancer. Curr Med Chem 2017; 24(13): 1321–1331.

15.

Rozengurt

. Mechanistic target of rapamycin (mTOR): a point of convergence in the action of insulin/IGF-1 and G protein-coupled receptor agonists in pancreatic cancer cells. Front Physiol 2014; 5: 357.

16.

Zitvogel

Pietrocola

Kroemer

. Nutrition, inflammation and cancer. Nat Immunol 2017; 18(8): 843–850.

17.

Johnson

Wei

Ensor

, et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control 2013; 24(6): 1207–1222.

18.

Gatenby

Caygill

Wall

, et al. Lifetime risk of esophageal adenocarcinoma in patients with Barrett’s esophagus. World J Gastroenterol 2014; 20(28): 9611–9617.

19.

Kirkegard

Mortensen

Cronin-Fenton

. Chronic pancreatitis and pancreatic cancer risk: a systematic review and meta-analysis. Am J Gastroenterol 2017; 112(9): 1366–1372.

20.

Padoan

Plebani

Basso

. Inflammation and pancreatic cancer: focus on metabolism, cytokines, and immunity. Int J Mol Sci 2019; 20(3): 676.

21.

Chia

Chen

. TGFbeta in T cell biology and tumor immunity: angel or devil? Cytokine Growth Factor Rev 2014; 25(4): 423–435.

22.

Kelly

Davison

Bliss

, et al. Macrophages in human breast disease: a quantitative immunohistochemical study. Br J Cancer 1988; 57(2): 174–177.

23.

Van Overmeire

Laoui

Keirsse

, et al. Mechanisms driving macrophage diversity and specialization in distinct tumor microenvironments and parallelisms with other tissues. Front Immunol 2014; 5: 127.

24.

Qian

Pollard

. Macrophage diversity enhances tumor progression and metastasis. Cell 2010; 141(1): 39–51.

25.

Zhang

Liu

Gong

, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 2012; 7(12): e50946.

26.

Kessenbrock

Plaks

Werb

. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141(1): 52–67.

27.

Mantovani

Sozzani

Locati

, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23(11): 549–555.

28.

Yang

Zhang

. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 2017; 10(1): 58.

29.

Condeelis

Pollard

. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006; 124(2): 263–266.

30.

Nielsen

Schmid

. Macrophages as key drivers of cancer progression and metastasis. Mediators Inflamm 2017; 2017: 9624760.

31.

Saio

Radoja

Marino

, et al. Tumor-infiltrating macrophages induce apoptosis in activated CD8(+) T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide. J Immunol 2001; 167(10): 5583–5593.

32.

Chang

Peng

, et al. Pancreatic cancer-derived small extracellular vesical Ezrin regulates macrophage polarization and promotes metastasis. Am J Cancer Res 2020; 10(1): 12–37.

33.

Zhang

Song

, et al. The emerging roles of exosomes in the chemoresistance of hepatocellular carcinoma. Curr Med Chem 2021; 28(1): 93–109.

34.

Zhang

Liu

Peng

, et al.

Pancreatic cancer-educated macrophages protect cancer cells from complement-dependent cytotoxicity by up-regulation of CD59

2019; 10(11): 836.

35.

Liu

, et al. Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment. Cancer Immunology, Immunotherapy 2020; 69(8): 1477–1492.

36.

Ireland

Luckett

Schmid

, et al.

Blockade of stromal gas6 alters cancer cell plasticity, activates NK cells, and inhibits pancreatic cancer metastasis

2020; 11: 297.

37.

Bulle

Dekervel

Deschuttere

, et al.

Gemcitabine Recruits M2-type tumor-associated macrophages into the stroma of pancreatic cancer

2020; 13(3): 100743.

38.

Osborne

Sundseth

Burks

, et al. Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment. Cancer Immunol Immunother 2019; 68(10): 1635–1648.

39.

Yoshii

Hayashi

Iijima

, et al. Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression. Cancer Sci 2019; 110(8): 2396–2407.

40.

Yang

, et al. Remodeling tumor immune microenvironment via targeted blockade of PI3K-γ and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy. J Controlled Release 2020; 321: 23–35.

41.

Zhang

Huang

Ding

, et al. Interferon gamma inhibits CXCL8-CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer. J ImmunoTherapy Cancer 2020; 8(1): e000308.

42.

Selders

Fetz

Radic

, et al. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen Biomater 2017; 4(1): 55–68.

43.

Mantovani

Cassatella

Costantini

, et al. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11(8): 519–531.

44.

Tak

Wijten

Heeres

, et al. Human CD62L(dim) neutrophils identified as a separate subset by proteome profiling and in vivo pulse-chase labeling. Blood 2017; 129(26): 3476–3485.

45.

Hellebrekers

Vrisekoop

Koenderman

. Neutrophil phenotypes in health and disease. Eur J Clin Invest 2018; 48(Suppl 2): e12943.

46.

Fridlender

Sun

Mishalian

, et al. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One 2012; 7(2): e31524.

47.

Jablonska

Leschner

Westphal

, et al. Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 2010; 120(4): 1151–1164.

48.

Piccard

Muschel

Opdenakker

. On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 2012; 82(3): 296–309.

49.

Coffelt

Wellenstein

de Visser

. Neutrophils in cancer: neutral no more. Nat Rev Cancer 2016; 16(7): 431–446.

50.

Bayne

Beatty

Jhala

, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012; 21(6): 822–835.

51.

Felix

Gaida

. Neutrophil-derived proteases in the microenvironment of pancreatic cancer -active players in tumor progression. Int J Biol Sci 2016; 12(3): 302–313.

52.

Zhan

Zhou

Cheng

, et al. Crosstalk between stromal cells and cancer cells in pancreatic cancer: new insights into stromal biology. Cancer Lett 2017; 392: 83–93.

53.

Wei

Zhang

, et al. Vimentin-positive circulating tumor cells as a biomarker for diagnosis and treatment monitoring in patients with pancreatic cancer. Cancer Lett 2019; 452: 237–243.

54.

Chao

Furth

Vonderheide

. CXCR2-dependent accumulation of tumor-associated neutrophils regulates T-cell immunity in pancreatic ductal adenocarcinoma. Cancer Immunol Res 2016; 4(11): 968–982.

55.

Zhang

Liu

Peng

, et al. CXCL5 overexpression predicts a poor prognosis in pancreatic ductal adenocarcinoma and is correlated with immune cell infiltration. J Cancer 2020; 11(9): 2371–2381.

56.

Oto

Navarro

Larsen

, et al. MicroRNAs and neutrophil activation markers predict venous thrombosis in pancreatic ductal adenocarcinoma and distal extrahepatic cholangiocarcinoma. Int J Mol Sci 2020; 21(3): 840.

57.

Bai

Yang

, et al. miR-135b delivered by gastric tumor exosomes inhibits FOXO1 expression in endothelial cells and promotes angiogenesis. Mol Ther 2019; 27(10): 1772–1783.

58.

Furze

Rankin

. Neutrophil mobilization and clearance in the bone marrow. Immunology 2008; 125(3): 281–288.

59.

Martin

Burdon

Bridger

, et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 2003; 19(4): 583–593.

60.

Fridlender

Albelda

. Tumor-associated neutrophils: friend or foe? Carcinogenesis 2012; 33(5): 949–955.

61.

Wang

Farooq

, et al. A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases. J Biol Chem 2012; 287(8): 5744–5755.

62.

Sano

Ijichi

Takahashi

, et al. Blocking CXCLs-CXCR2 axis in tumor-stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment. 2019; 8(2): 8.

63.

Wang

Wei

, et al. Tumor-derived exosomes induce PD1(+) macrophage population in human gastric cancer that promotes disease progression. Oncogenesis 2018; 7(5): 41.

64.

Apte

Pirola

Wilson

. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 2012; 3: 344.

65.

Watari

Hotta

Mabuchi

. Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn 1982; 58(4–6): 837–858.

66.

Ikejiri

. The vitamin A-storing cells in the human and rat pancreas. Kurume Med J 1990; 37(2): 67–81.

67.

Zha

Jones

, et al. Isolation and characterization of human islet stellate cells. Exp Cell Res 2016; 341(1): 61–66.

68.

Wang

Chen

, et al. A transcriptional sequencing analysis of islet stellate cell and pancreatic stellate cell. J Diabetes Res 2018; 2018: 7361684.

69.

Riopel

Liu

, et al. beta1 integrin-extracellular matrix interactions are essential for maintaining exocrine pancreas architecture and function. Lab Invest 2013; 93(1): 31–40.

70.

Liu

Jiang

Zhao

, et al. Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma. J Exp Med 2019; 216(3): 656–673.

71.

Jiang

Bai

Qin

, et al. NGF from pancreatic stellate cells induces pancreatic cancer proliferation and invasion by PI3K/AKT/GSK signal pathway. J Cell Mol Med 2020; 24(10): 5901–5910.

72.

Cave

Guida

Costa

, et al. TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation. Oncogene 2020; 39(21): 4271–4285.

73.

Steins

van Mackelenbergh

van der Zalm

, et al. High-grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF-1. EMBO Reports 2020; 21(5): e48780.

74.

Zhao

Chen

. Exosomes from CD133(+) cells carrying circ-ABCC1 mediate cell stemness and metastasis in colorectal cancer. J Cell Biochem 2020; 121(5–6): 3286–3297.

75.

Xue

Jia

Wang

, et al. A rising star in pancreatic diseases: pancreatic stellate cells. Front Physiol 2018; 9: 754.

76.

Jaster

. Molecular regulation of pancreatic stellate cell function. Mol Cancer 2004; 3: 26.

77.

Liu

Zhang

Zhou

, et al. Cancer associated fibroblasts-derived exosomes contribute to radioresistance through promoting colorectal cancer stem cells phenotype. Exp Cell Res 2020; 391(2): 111956.

78.

Bachem

Zhou

Buck

, et al. Pancreatic stellate cells--role in pancreas cancer. Langenbecks Arch Surg 2008; 393(6): 891–900.

79.

Takikawa

Masamune

Yoshida

, et al. Exosomes derived from pancreatic stellate cells: microRNA signature and effects on pancreatic cancer cells. Pancreas 2017; 46(1): 19–27.

80.

Tian

Cai

, et al. Activation of pancreatic stellate cells involves an EMT-like process. Int J Oncol 2016; 48(2): 783–792.

81.

Vonlaufen

Phillips

, et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 2010; 177(5): 2585–2596.

82.

Tozzi

Sørensen

Magni

, et al. Proton pump inhibitors reduce pancreatic adenocarcinoma progression by selectively targeting H, K-ATPases in pancreatic cancer and stellate cells. Cancers 2020; 12(3): 640.

83.

Xie

Hang

Wang

, et al. Stromal modulation and treatment of metastatic pancreatic cancer with local intraperitoneal triple miRNA/siRNA nanotherapy. ACS Nano 2020; 14(1): 255–271.

84.

Tjomsland

Sandnes

Pomianowska

, et al. The TGFβ-SMAD3 pathway inhibits IL-1α induced interactions between human pancreatic stellate cells and pancreatic carcinoma cells and restricts cancer cell migration. J Exp Clin Cancer Res 2016; 35(1): 122.

85.

Pothula

Goldstein

, et al. Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis. Br J Cancer 2020; 123(9): 1466.

86.

Wang

Zhan

Huynh

, et al. Inhibition of PAK1 suppresses pancreatic cancer by stimulation of anti-tumour immunity through down-regulation of PD-L1. Cancer Lett 2020; 472: 8–18.

87.

Robinson

. Granulocytosis in neoplasia. Ann N Y Acad Sci 1974; 230: 212–218.

88.

Bennett

Rao

Mitchell

. Systemic bacillus Calmette-Guerin (BCG) activates natural suppressor cells. Proc Natl Acad Sci U S A 1978; 75(10): 5142–5144.

89.

Slavin

Strober

. Induction of allograft tolerance after total lymphoid irradiation (TLI): development of suppressor cells of the mixed leukocyte reaction (MLR). J Immunol 1979; 123(2): 942–946.

90.

Gabrilovich

Bronte

Chen

, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res 2007; 67(1): 425.

91.

Gabrilovich

Ostrand-Rosenberg

Bronte

. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12(4): 253–268.

92.

Dumitru

Moses

Trellakis

, et al. Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology. Cancer Immunol Immunother 2012; 61(8): 1155–1167.

93.

Sica

Porta

Amadori

, et al. Tumor-associated myeloid cells as guiding forces of cancer cell stemness. Cancer Immunol Immunother 2017; 66(8): 1025–1036.

94.

Cui

Kryczek

Zhao

, et al. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 2013; 39(3): 611–621.

95.

Albini

Bruno

Noonan

, et al. Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol 2018; 9: 527.

96.

Dolcetti

Peranzoni

Ugel

, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 2010; 40(1): 22–35.

97.

Trovato

Fiore

Sartori

, et al. Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3. J ImmunoTherapy Cancer 2019; 7(1): 255.

98.

Yin

Huang

, et al. Macrophage-derived exosomal microRNA-501-3p promotes progression of pancreatic ductal adenocarcinoma through the TGFBR3-mediated TGF-beta signaling pathway. J Exp Clin Cancer Res 2019; 38(1): 310.

99.

Turbitt

Collins

Meng

, et al. Increased adiposity enhances the accumulation of MDSCs in the tumor microenvironment and adipose tissue of pancreatic tumor-bearing mice and in immune organs of tumor-free hosts. Nutrients 2019;11(12): 3012.

100.

Reyes

Teller

Muckenhuber

, et al. Neoadjuvant therapy remodels the pancreatic cancer microenvironment via depletion of protumorigenic immune cells. Clin Cancer Res 2020; 26(1): 220–231.

101.

Sun

Zhou

Fang

, et al. Colorectal cancer exosomes induce lymphatic network remodeling in lymph nodes. Int J Cancer 2019; 145(6): 1648–1659.

102.

Dong

Sun

, et al. Serum membrane type 1-matrix metalloproteinase (MT1-MMP) mRNA protected by exosomes as a potential biomarker for gastric cancer. Med Sci Monit 2019; 25: 7770–7783.

103.

Totiger

Srinivasan

Jala

, et al. Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. Mol Cancer Ther 2019; 18(2): 301–311.

104.

Oleinika

Nibbs

Graham

, et al. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol 2013; 171(1): 36–45.

105.

Finotello

Trajanoski

. New strategies for cancer immunotherapy: targeting regulatory T cells. Genome Med 2017; 9(1): 10.

106.

Wang

Lang

Zhao

, et al. Cancer-FOXP3 directly activated CCL5 to recruit FOXP3Treg cells in pancreatic ductal adenocarcinoma. Oncogene 2017; 36(21): 3048–3058.

107.

Jang

Hajdu

Liot

, et al. Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep 2017; 20(3): 558–571.

108.

Cheng

Luo

Jin

, et al. Kras mutation correlating with circulating regulatory T cells predicts the prognosis of advanced pancreatic cancer patients. Cancer Med 2020; 9(6): 2153–2159.

109.

Madondo

Quinn

Plebanski

. Low dose cyclophosphamide: mechanisms of T cell modulation. Cancer Treat Rev 2016; 42: 3–9.

110.

Burks

Fleury

Livingston

, et al. ISG15 pathway knockdown reverses pancreatic cancer cell transformation and decreases murine pancreatic tumor growth via downregulation of PDL-1 expression. Cancer Immunol Immunother 2019; 68(12): 2029–2039.

111.

Perez-Santos

Anaya-Ruiz

Herrera-Camacho

, et al. Bispecific anti-OX40/CTLA-4 antibodies for advanced solid tumors: a patent evaluation of WO2018202649. Expert Opin Ther Patents 2019; 29(12): 921–924.

112.

Doi

Fujiwara

Koyama

, et al. Phase I study of the bifunctional fusion protein bintrafusp Alfa in Asian patients with advanced solid tumors, including a hepatocellular carcinoma safety-assessment cohort. The Oncologist 2020; 25(9): e1292–e1302.

113.

Wang

Yin

Tian

, et al. Granulocytic myeloid-derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9. Adv Sci (Weinh) 2019; 6(18): 1901278.

114.

Jing

McAllister

Vonderhaar

, et al. STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models. J ImmunoTherapy Cancer 2019; 7(1): 115.

115.

Lennon

Oweida

Milner

, et al. Pancreatic tumor microenvironment modulation by EphB4-ephrinB2 inhibition and radiation combination. Clin Cancer Res 2019; 25(11): 3352–3365.

116.

Dai

Han

Liu

, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 2020; 16(11): 2069–2083.

Immune cell responses in pancreatic cancer and their clinical application

Abstract

Keywords

Introduction

Tumor-associated macrophages

Interaction between TAMs and pancreatic cancer cells

The clinical application of TAMs in the treatment of pancreatic cancer

Tumor-associated neutrophils

Interaction between Tumor-associated neutrophils and pancreatic cancer cells

Clinical applications relevant to Tumor-associated neutrophils in pancreatic cancer

Pancreatic stellate cells

The interaction between Pancreatic stellate cells and pancreatic cancer

The clinical application of Pancreatic stellate cells in the treatment of Pancreatic cancer

Myeloid-derived suppressor cells

The interaction between Myeloid-derived suppressor cells and pancreatic cancer

The relevant clinical application of Myeloid-derived suppressor cells in pancreatic cancer

Regulatory T cells

The interaction between Treg cells and PC cells

The relevant clinical application of Treg cells in PDAC

Conclusion

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

References