Pancreatic cancer (PC) is an aggressive and damaging disease characterized by invasiveness, fast progression, and profound resistance to treatment. Despite the low incidence of PC relative to other cancers, it is considered one of the most mortal in most developed countries. Unfortunately, PC has nonspecific symptoms in the early stages and, as such, it is always diagnosed at an advanced stage, when the treatment is generally ineffective. Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of PC cases, is one of the most aggressive malignancies, with poor response of tumors to conventional therapeutic intervention chemotherapy and radiotherapy. Surgical resection offers the only chance of a cure for nonmetastatic PC. However, only 10%-20% of patients have potentially resectable disease at diagnosis.

Macrophages and PC

M1-polarized macrophages are predominant in acute pancreatitis, while M2 polarized macrophages have a prominent role in chronic pancreatitis. It is thought that tumor-associated macrophages (TAMs) infiltrating solid tumors such as PDAC, have similar characteristics to M2 types and correlate with poor prognosis. The level of M2 converted macrophages in PC was higher than that in chronic pancreatitis. Moreover, M2 macrophages were associated with local recurrence and survival in patients with PC.

The Roles of TAMs in PC

• Promoting Angiogenesis: PC is characterized by heterogeneous vessel distribution and marked hypoperfusion. TAMs and secreted cytokines can increase the number of blood vessels and vascular permeability, resulting in the metastasis of PC cells. Suppression of TAMs is an effective measure to inhibit angiogenesis and reduce tumor cell migration in PC.
• Immune Escape: TAMs can mediate PC cells to immune escape by releasing immunosuppressive cytokines, inhibiting the activity of tumor-infiltrating immune cells, and facilitating other inhibitory cells.
• Metastasis: Epithelial-mesenchymal transition (EMT) decreases cell adherence, increasing invasiveness and migratory ability. Proinflammatory cytokines from macrophages and tumor cells serve as major inducers of EMT programs. Therefore, EMT acts as a pivotal bridge linking inflammation-related cells, such as macrophages, and cancer cells in the promotion of PC formation and metastasis.
• Chemotherapy resistance: TAMs are known to be one of the main subsets of immune cells infiltrating pancreatic tumors, and depletion of macrophages can restrict growth and distant metastasis of PC as well as increase sensitivity to chemotherapy drugs. It is reported that TAMs can secrete an antiapoptotic factor to inhibit apoptosis or upregulate the expression of cytidine deaminase (CDA), thereby resulting in PC chemoresistance.

Clinical Implications of TAMs in PDAC

Approximately 80% of tumors have shown a positive correlation between the poor prognosis and TAM, while only tumors less than 10% of TAM density demonstrated a good prognosis. M2-polarized macrophages (identified by CD163 immunopositivity) were significantly more abundant in primary PDAC samples, compared to the paired adjacent normal tissues and those diagnosed as chronic pancreatitis. The presence of M2 polarized TAM in the stroma are strongly correlated with the tumors located in the tail and body of the pancreas, and higher counts of M2-polarized TAM were associated with increased risk of lymph node metastasis, neural invasion, chemoresistance, and hence the worse prognosis and survival in PDAC.

Therapies of Targeting TAMs in PC

Immunoprevention and immunotherapy by developing effective chemoprevention and therapeutic agents that can achieve an optimal balance between pro- and anti-tumor macrophage activities provide an opportunity for pancreatic cancer prevention and treatment. These strategies are described below.

• Inhibiting monocyte/macrophage recruitment: Targeting the chemokine ligand 2 (CCL2)/chemokine receptor 2 (CCR2) (CCL2/CCR2) axis is promising as it results in blocking mobilization of monocytes from the bone marrow to the blood, which results in preventing their recruitment to the tumor.
• Targeting macrophage activation: Colony-stimulating factor (CSF-1) has been involved in the recruitment of monocytes into the tumor. Substantial evidence indicates that suppression of CSF-1/CSF-1 receptor signaling is one of the most advanced approaches to target macrophage activation. In human PC, CSF-2 is prominently expressed, compared to CSF-1. Therefore, Targeting CSF-2/CSF-2R signaling may be more efficient for PC immunotherapy.
• Increasing antitumor macrophages by reprogramming macrophage polarization: TLR agonists, anti-CD40 mAbs, Peroxisome proliferator-activated receptor (PPAR)-γ agonists (thiazolidinediones), targeting HRG and its Fcγ receptors can Reprogram tumor-infiltrating myeloid cells towards an antitumor phenotype.
• Decreasing survival of TAMs: Folate receptor-β (FR-β) originally detected in the placenta, spleen, bone marrow, and thymus has recently been shown to be over-expressed on TAM, indicating that it might be a good target for decreasing survival of TAM. In addition, 5-fluorouracil and docetaxel are found to have unique properties of selectively depleting M2 macrophages.

Fig.1 Agents targeting TAM in pancreatic cancer.^1,2

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References

1. Cui, Ran, et al. "Targeting tumor-associated macrophages to combat pancreatic cancer." Oncotarget 7.31 (2016): 50735.
2. Under Open Access license CC BY, without modification.
3. Yang, S.; et al. Tumor-associated macrophages in pancreatic ductal adenocarcinoma: origin, polarization, function, and reprogramming. Frontiers in Cell and Developmental Biology. 2020, 8:607209
4. Cui, R.; et al. Targeting tumor-associated macrophages to combat pancreatic cancer. Oncotarget. 2016, 7(31): 50735-50754.