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.

Keywords: TAM; anti-cancer treatment; immune landscape; immunotherapy.; reprogramming of TAM.

Figure 1

Tumor-associated macrophages (TAMs) and their ambivalent role in shaping the tumor microenvironment. On the left side, the anti-tumoral M1-like macrophages, stimulated by immunostimulatory cytokines (e.g., IL-1β, IL-12, IL-23, TNF-α, IFN-γ). M1-like TAMs promote the recruitment and activation of T cells by producing CXCL10, TNF-α, and other cytokines. Through the release of TNF-α, ROS (Reactive Oxign Species), and NO, they can directly kill tumor cells. M1-like macrophages induce tissue damage, maturation of APCs (Antigen Presenting Cell) and they can actively phagocytose cancer cells. On the right side, the pro-tumoral M2-like macrophages, release immuno-suppressive mediators, such as IL-10, TGF-β, IDO1/2, which support regulatory T cells. These pro-tumoral immune cells promote tumor proliferation (EGF, FGF, PDGF), angiogenesis (CXCL8, VEGF, FGF), invasion and metastasis (TGF-β), and a continuous tissue remodeling (MMPs, cathepsins, uPAR).

Figure 2

Reprogramming of tumor-associated macrophages is a promising target for novel anti-tumor treatments. This figure summarizes and gives examples of various strategies with this purpose. The inhibition of immunosuppressive genes has been investigated through the delivery of the CRISPR/Cas9 machinery or lentiviral vectors to directly edit TAMs genome, HDAC inhibitors for epigenetic regulation or nanoparticles encapsulating siRNAs, miRNAs, or mRNAs to manipulate gene transcription. TLR and STING agonists have been shown to reprogram TAMs towards an M1-like phenotype. Monoclonal antibodies targeting the CD47/SIRPα axis, activating CD40, or blocking the scavenger receptor MARCO activate the antitumoral functions of macrophages. Traditional chemotherapeutics such as gemcitabine or doxorubicin, oncolytic viruses, and low doses of radiation, which induce the release of DAMPs by tumor cells, have been reported to polarize macrophages towards M1-like phenotype, through pattern recognition receptor stimulation. Manipulation of TAMs metabolism has been modestly explored, showing good results in experimental settings through the inhibition of glycolysis, hypoxia, lactate, cholesterol, IDO, arginase, glutamine, or adenosine pathways in macrophages, but also by the administration of iron-based nanoparticles (NPs) (Ferumoxytol^®) or oxygen. cGAMP, cyclic guanosine monophosphate–adenosine monophosphate; CpG ODNs, CpG oligodeoxynucleotides; DAMP, damage-associated molecular pattern; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; HDAC, histone deacetylase; MARCO, macrophage receptor with collagenous structure; PRR, pattern recognition receptors; R848, resiquimod; STING, stimulator of interferon genes; TAM, tumor-associated macrophage; TLRs, toll-like receptors.