Abstract
Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I). Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy.
Highlights
Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the tumor microenvironment [1, 2]
In the second phase of priming, type I IFN (IFN-α, IFN-β) and type II IFN (IFN-γ) modulate the production of chemokines from TAMs, suggesting that these cytokines repolarize TAMs in several skin cancers [7, 18]. Cancer stromal factors such as soluble receptor activator of nuclear factor kappa-B ligand (RANKL) derived from cancer cells could be a third mode of stimulation that activates mature M2 macrophages to produce a series of chemokines that recruit immunosuppressive cells such as Tregs and Th2, leading to maintenance of the tumor microenvironment [8, 10, 17]
Other reports have suggested that a series of chemokines (CCL17, CXCL10, CCL4, and IL-8) in cerebrospinal fluid may be useful for predicting brain metastasis in melanoma patients [21]
Summary
Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the tumor microenvironment [1, 2]. TAMs express immune checkpoint modulators [e.g., B7 family, B7-homolog family including programmed death ligand 1 (PD-L1)] [3] that directly suppress activated T cells. TAMs produce various chemokines that attract other immunosuppressive cells such as Tregs, myeloid-derived suppressor cells (MDSCs), and type 2 helper (Th2) T cells, which maintain the immunosuppressive factors of the tumor microenvironment [1, 2, 4]. It may be possible to repolarize TAMs into anti-tumor macrophages, such as M1-phenotype macrophages, to suppress tumor progression by modifying the profiles of tumor-infiltrating lymphocytes (TILs) [7, 18, 19].
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