Targeting tumor-associated macrophages to combat pancreatic cancer

Abstract

The tumor microenvironment is replete with cells that evolve with and provide support to tumor cells during the transition to malignancy. The hijacking of the immune system in the pancreatic tumor microenvironment is suggested to contribute to the failure to date to produce significant improvements in pancreatic cancer survival by various chemotherapeutics. Regulatory T cells, myeloid derived suppressor cells, and fibroblasts, all of which constitute a complex ecology microenvironment, can suppress CD8+ T cells and NK cells, thus inhibiting effector immune responses. Tumor-associated macrophages (TAM) are versatile immune cells that can express different functional programs in response to stimuli in tumor microenvironment at different stages of pancreatic cancer development. TAM have been implicated in suppression of anti-tumorigenic immune responses, promotion of cancer cell proliferation, stimulation of tumor angiogenesis and extracellular matrix breakdown, and subsequent enhancement of tumor invasion and metastasis. Many emerging agents that have demonstrated efficacy in combating other types of tumors via modulation of macrophages in tumor microenvironments are, however, only marginally studied for pancreatic cancer prevention and treatment. A better understanding of the paradoxical roles of TAM in pancreatic cancer may pave the way to novel preventive and therapeutic approaches. Here we give an overview of the recruitment and differentiation of macrophages, TAM and pancreatic cancer progression and prognosis, as well as the potential preventive and therapeutic targets that interact with TAM for pancreatic cancer prevention and treatment.

Keywords: chemoprevention; pancreatic cancer; tumor microenvironment; tumor-associated macrophages.

Figure 1. Dual role of macrophages in the response to stimuli in tumor microenvironment

Briefly, stimuli that polarize macrophages are divided into membrane receptors, cytokines and its receptors, chemokines and its receptors, and effector molecules. The majority of molecules listed above are secreted by both M1- and M2-TAM. However, the phenotype of TAM may vary during different stages of tumor progression, resulting in differential stimuli density in M1- or M2-TAM. Arg, arginase; CCL, C-C chemokine ligand; GM-CSF, granulocyte macrophage colony-stimulating factor; HIF, hypoxia-inducible factor; HRG, histidine-rich glycoprotein; IFN-γ, interferon-γ; IL, interleukin; M-CSF, macrophage colony-stimulating factor; MR, mannose receptor; NOS, nitric oxide synthase; TAM, tumor-associated macrophages; TGF, transforming growth factor; TLR, toll-like receptor; TNF, tumor necrosis factor.

Figure 2. Schematic representation of cells and mediators influencing the function of TAM and tumor progression in pancreatic cancer

TAM can release a panel of mediators facilitating lymphangiogenesis, angiogenesis, EMT, immune suppression, and tumorigenicity of CSC, which provide a permissive environment for pancreatic tumor progression. Ang-2, angiopoietin-2; CSC, cancer stem cells; EMT, epithelial-mesenchymal transition; FGF, fibroblast growth factor; ISG-15, interferon-stimulated gene 15; MDSC, myeloid-derived suppressor cells; MFG-E8, milk-fat globule-epidermal growth factor-VIII; MIF, migration inhibitory factor; MMP, matrix metalloproteinases; NK, nature killer; NOS, nitric oxide synthase; PD, programmed death; PDA, pancreatic ductal adenocarcinoma; TAM, tumor-associated macrophage; TEM, Tie2-expressing monocytes; TGF, transforming growth factor; TP, thymidine phosphorylase; Treg, regulatory T cells.

Figure 3. Agents targeting TAM in pancreatic cancer

Multiple agents and strategies to target TAM as indicated here or referenced throughout the review are at different stages of clinical development for pancreatic cancer prevention and treatment. Ab, antibody; FR-α, folate receptor-α; TLR, Toll-like receptors.