Seminar Article
Development and translation of novel therapeutics targeting tumor-associated macrophages

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Abstract

Tumor-associated macrophages (TAMs) regulate an array of tumor functions and have critical roles in both the progression and the eradication of cancer. Numerous therapies targeting TAMs are under development in cancer and many have demonstrated success at the preclinical and clinical levels. Most of these therapies fall within 3 main categories: systemic depletion of TAMs, inhibition of TAM recruitment and polarization, and promoting the antitumor functions of TAMs. In this article, the rationale behind these various therapies and approaches is reviewed along with supporting preclinical and clinical data.

Introduction

Macrophages are myeloid immune cells with integral roles in a wide range of physiologic processes. Within these roles, macrophages can perform a diverse range of functions, including matrix remodeling, growth factor secretion, angiogenesis, pathogen eradication, and immune regulation [1], [2], [3], [4], [5], [6], [7]. In cancer, this broad functional capacity enables critical roles in both tumor progression and tumor destruction. These roles are dependent on their phenotype, which are grouped into 2 main categories, termed M1 and M2. M1 macrophages support tumor eradication through stimulation of innate and adaptive immune responses. M2 macrophages promote tumor growth, invasion, and therapeutic resistance through their roles in growth factor secretion, angiogenesis, and immune suppression. Within the tumor microenvironment (TME), the phenotype of these tumor-associated macrophages (TAMs) is regulated in large part by an array of factors, which are secreted by tumor, immune, and stromal cells as well as physical interactions with the extracellular matrix.

In both solid and hematologic malignancies, the extent of TAM infiltration within the TME as well as the predominant TAM phenotype has direct correlation with patient outcomes [8]. In cancers where TAMs are predominantly of the M2 phenotype, increased TAM infiltration is associated with more advanced disease at diagnosis as well as worse progression-free survival (PFS) and overall survival (OS) [9]. However, when TAMs are skewed more toward an M1 phenotype, their infiltration is associated with better cancer-related outcomes, including a decreased risk of death.

Given their numerous tumor supportive functions, their potential antitumor properties, and their strong correlation with patient outcomes, TAMs represent an attractive therapeutic target with vast potential. A number of approaches for targeting TAMs in cancer are under investigation and have demonstrated success at both the preclinical and clinical levels.

Section snippets

Systemic depletion of TAMs

Several TAM-directed strategies have focused on the systemic depletion of monocyte/macrophage populations through the administration of compounds that have macrophage-selective toxicity. Among these is trabectedin, a DNA binding agent that promotes apoptosis of macrophages through tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptors 1 and 2 [10]. In both Europe and the United States, trabectedin has been approved for treatment of sarcomas based on improvements in PFS and

Targeting recruitment and reprogramming

Aiming to limit or even alter the role of macrophages within the TME, multiple TAM-directed strategies have focused on targeting the pathways involved in TAM recruitment and polarization. One of the most extensively studied targets of macrophage recruitment is the CCL2. CCL2 is a chemokine that is secreted by cells within the TME that recruits TAMs into tumors through interaction with the macrophage CCR2 receptor. Targeting CCL2 has shown considerable promise at the preclinical level, resulting

Supporting the antitumor functions of TAMs

Direct phagocytosis of malignant cells is an important mechanism of TAM-mediated tumor eradication [25]. Unfortunately, tumor cells are able to avoid this method of destruction through up-regulation of surface receptors, such as CD47, which inhibit macrophage phagocytic activity [39]. Multiple therapies are under development, which target this defense mechanism by tumors. This includes monoclonal antibodies, which can block surface CD47. At the preclinical level, administration of these agents

Discussion

While tumor-directed therapies such as hormone therapies, chemotherapies, and radiation therapies remain the foundation of cancer treatment, therapies that target the TME are rapidly becoming an invaluable component of oncologic care. This includes genitourinary malignancies, where a number of these therapies are now standard of care and even frontline treatments. Notable examples include checkpoint inhibitors in renal and bladder cancers, antiangiogenic agents in renal cell carcinoma, and

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    Disclosures: The authors have no relevant financial disclosures.

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