Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Abstract

: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.

Keywords: cancer immunotherapy; clinical trials; immune suppression; immune system; tumor microenvironment; tumor-associated macrophages.

Figure 1

Anti-tumor and pro-tumor functions of tumor-associated macrophages (TAMs). A key feature of macrophages is their intrinsic plasticity, the two extremes of which have been identified as M1-like and M2-like polarization. In the tumor microenvironment, several molecular pathways have been recognized which drive and maintain the phenotypes and functions of TAMs. On the left side, M1-like macrophages, with anti-tumor functions, can be stimulated by immunostimulatory cytokines such as IL-1b, IL-12, IL-23, TNF-alfa, and IFNγ; MHCII molecules and IL-12 are required for efficient antigen presentation. M1-like TAMs produce chemokines, such as CXCL10, that promotes the recruitment and activation of T cells. In addition, M1-like-TAMs actively phagocytose tumor cells and release TNF-alfa, ROS, and NO for the direct killing of cancer cells. On the right, M2-like macrophages, with pro-tumor functions, are conditioned by the hypoxic tumor micro-environment and by immuno-suppressive mediators (IL-10, TGFβ). M2-like-TAMs secrete molecules to promote angiogenesis (CXCL8, VEGF), tumor proliferation (EGF, FGF, PDGF), induce epithelial-mesenchymal-transition (TGFβ), and continuous matrix remodeling (MMPs, cathepsins, uPAR). Several immuno-suppressive molecules are produced (IL-10, TGFβ, IDO1/2), which support regulatory T cells.

Figure 2

Summary of available therapeutic strategies to target TAMs. On the left side are different approaches to kill macrophages or inhibit their recruitment in tumors. Monoclonal antibodies or kinase inhibitors have been developed to disrupt the CSF-1/CSF-1R, CCL2/CCR2, or the CXCL12/CXCR4 axis required for the recruitment of new macrophages towards the tumor. Traditional bisphosphonates free or loaded into nanocarriers, and also trabectedin are chemotherapeutics, which showed preferential toxicity towards monocytes/macrophages and have been used to reduce their number in tumors. On the right side are strategies to reprogram TAMs into M1-like anti-tumor effectors. Monoclonal agonist antibodies to CD40 or agonists to Toll-like receptors activate TAMs. SIRP1α inhibitors prevent the block of phagocytosis; mAbs against immune checkpoint ligands, such as PD-L1, can also target TAMs. RNA-based therapies and some small drugs inhibiting histone acetylation (HDAC) or the PI3Kgamma pathway are also under evaluation.