Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

Abstract

In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapies.

Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma

“…Furthermore, myeloid cell subsets such as myeloid-derived suppressor cells, dendritic cells, tumor-associated macrophages (TAMs), and tumor-associated neutrophils in the TIME were not investigated although myeloid cells in tumors are considered to play a crucial role in the control of tumor growth and progression [ 46 , 47 , 48 ]. TAMs inhibit immuno-stimulatory signals and are implicated in the initiation and progression of the tumor, through the secretion of signaling molecules, such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), macrophage colony-stimulating factor (M-CSF), interleukins or chemokines (IL-10, IL-6, and CXCL-8) [ 49 ]. Factors secreted by TAMs, such as TGF-β, VEGF, CCL8, COX-2, MMP9, and MMP2 also contribute to the metastatic properties of cancer cells.…”

Macrophages in Osteosarcoma Immune Microenvironment: Implications for Immunotherapy

“…TLRs are essential pathogen recognition receptors expressed by antigen-presenting cells, including macrophages. TLRs agonists induce the conversion of M2 to M1 phenotype to elicit anti-tumor effects (122,123). For instance, Vidyarthi et al reported the administration of TLR-3 ligand [poly (I: C)] in the murine colon tumor skewed the M2-macrophages to M1-phenotype and regressed the tumor growth in the IFN-ab signaling pathwaydependent manner (124).…”

“…TLRs are essential pathogen recognition receptors expressed by antigen-presenting cells, including macrophages. TLRs agonists induce the conversion of M2 to M1 phenotype to elicit anti-tumor effects ( 122 , 123 ). For instance, Vidyarthi et al.…”

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

“…Originally suggested to be simplified as macrophages, the phenotypic dichotomy assigned to T-helper cells (Th1/Th2), the M1/M2 denominations of macrophages, were later described by Mantovani et al as the two extreme poles of a continuum of phenotypes and functions which could be acquired by very plastic immune cells [ 46 ]. In this outline, classically activated M1-like macrophages present a prototypical pro-inflammatory response and anti-tumor functions, while alternatively, activated M2-like macrophages, resembling tumor associated macrophages (TAMs), present anti-inflammatory properties, at the same time as supporting tumor progression, angiogenesis and metastasis and last of all, prevent adaptive immune responses [ 47 ].…”