Tumor-Associated Macrophages: Recent Insights and Therapies

Abstract

Macrophages, which have functions of engulfing and digesting foreign substances, can clear away harmful matter, including cellular debris and tumor cells. Based on the condition of the internal environment, circulating monocytes give rise to mature macrophages, and when they are recruited into the tumor microenvironment and in suitable conditions, they are converted into tumor-associated macrophages (TAMs). Generally, macrophages grow into two main groups called classically activated macrophages (M1) and alternatively activated macrophages (M2). M2 and a small fraction of M1 cells, also known as TAMs, not only lack the function of phagocytizing tumor cells but also help these tumor cells escape from being killed and help them spread to other tissues and organs. In this review, we introduce several mechanisms by which macrophages play a role in the immune regulation of tumor cells, including both killing factors and promoting effects. Furthermore, the targeted therapy for treating tumors based on macrophages is also referred to in our review. We confirm that further studies of macrophage-focused therapeutic strategies and their use in clinical practice are needed to verify their superior efficacy and potential in cancer treatment.

Keywords: immunity; immunity therapy; macrophages; tumor-associated macrophages; tumors.

Figure 1

The two main subpopulations of macrophages and TAMs. Macrophages can be classified to several subpopulations, and the two main subpopulations are classically activated macrophages (M1) and alternatively activated macrophages (M2). M1 macrophages, active by IFNγ, GM-CSF, other cytokines and LPS, play an important role in human immune function and contribute to tissue destruction by producing proinflammatory cytokines with strong killing effects on pathogens. M2 macrophages, that can be active by CSF-1, IL-4, IL-13, IL-10, and other stimulation, participate in parasite infection, tissue remodeling, allergic diseases, and angiogenesis, and play an important role in above processes. TAMs, recruited in tumor microenvironment, are not a typical kind of macrophages and different from M1 or M2. They express special TAM receptors on membrane, and are interacted with tumor cells and play the dual role in tumor microenvironment.

Figure 2

The role of tumor-associated macrophages (TAMs) in promoting tumor progression and related mechanisms. TAMs can secrete chemokines and cytokines that promote tumor development, such as IL-6, IL-8, and IL-10. Furthermore, various molecular mechanisms play a large role in immunosuppression. The PD-1/L1 signaling pathway promotes the possibility of tumor immune escape because it can inhibit the normal function of macrophages. The SIRPα/CD47 pathway is referred to as the “do-not-eat-me” signal, while tumor cells with CD47 expression can be recognized as self-normal cells. LILRB1/MHC class I component β2-microglobulin is also a significant mechanism of tumor escape. In breast cancer and ovarian cancer, CD 24 on tumor cells can promote immune escape through the interaction of Siglec-10. In addition, recent researchers have found that TAMs can promote the development of tumors through exosomes.

Figure 3

The two important treatment strategies targeting SIRPα/CD47 and LILRB1/MHC I. (A) CD47 is identified as a marker of self, or as a signal of “do-not-eat-me,” when the CD47 molecule of tumor cells is combined with its receptor, SIRPα, which is expressed on TAMs, and when MHC I on tumors is recognized by LILRB1 on TAMs; the signals will inhibit the phagocytosis of macrophages, promoting the occurrence, and development of tumors. (B) When using drugs such as monoclonal antibodies (anti-CD47 mAb, anti-SIRPα mAb, or anti-LILRB1 mAb), the recognition pathways are blocked, and the phagocytosis of macrophages is enhanced. Furthermore, the better treatment effect occurs when both pathways are blocked. (C) As it was discovered earlier that knocking out LILRB1 genes can cause macrophages to kill tumor cells, it could be predicted that more genetic modification of macrophages, such as making the SIRPα gene silent to suppress its expression, can achieve a similar effect.