Targeting Macrophages in Cancer: From Bench to Bedside

Abstract

Macrophages are a major component of the tumor microenvironment and orchestrate various aspects of immunity. Within tumors, macrophages can reversibly alter their endotype in response to environmental cues, including hypoxia and stimuli derived from other immune cells, as well as the extracellular matrix. Depending on their activation status, macrophages can exert dual influences on tumorigenesis by either antagonizing the cytotoxic activity immune cells or by enhancing antitumor responses. In most solid cancers, increased infiltration with tumor-associated macrophages (TAMs) has long been associated with poor patient prognosis, highlighting their value as potential diagnostic and prognostic biomarkers in cancer. A number of macrophage-centered approaches to anticancer therapy have been investigated, and include strategies to block their tumor-promoting activities or exploit their antitumor effector functions. Integrating therapeutic strategies to target TAMs to complement conventional therapies has yielded promising results in preclinical trials and warrants further investigation to determine its translational benefit in human cancer patients. In this review, we discuss the molecular mechanisms underlying the pro-tumorigenic programming of macrophages and provide a comprehensive update of macrophage-targeted therapies for the treatment of solid cancers.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Macrophages are characterized by their plasticity and heterogeneity. They can be activated by different types of stimuli (growth factors, cytokines, microbial products, nucleotides) which in turn will affect macrophages differently (Poh and Ernst, 2018). In vitro, the stimulation of macrophages by interferon-g (IFN-g) and/or lipopolysaccharides (LPS) induces the classical (M1) macrophage polarization (Nielsen and Schmid, 2017).…”

CAR T cells for brain tumors: Lessons learned and road ahead

“…Tumor‐ associated myeloid cells are frequently polarized toward a pro‐tumoral phenotype, and in combination with regulatory T cells, produce immunosuppressive cytokines/ligands including TGFβ, IL‐4, IL‐10, Arg1, IDO and PD‐L1 . Strategies to limit myeloid recruitment or reprogram the myeloid populations have been proven beneficial . In preclinical studies, blockade of colony stimulating factor receptor (CSFR; a receptor exclusively expressed by myeloid cells) on glioma xenografts enhanced anti‐tumor response to radiotherapy by reducing the recruitment of bone marrow‐derived macrophages .…”

“…159 Strategies to limit myeloid recruitment or reprogram the myeloid populations have been proven beneficial. 160 In preclinical studies, blockade of colony stimulating factor receptor (CSFR; a receptor exclusively expressed by myeloid cells) on glioma xenografts enhanced anti-tumor response to radiotherapy by reducing the recruitment of bone marrow-derived macrophages. 161 Additionally, inhibiting STAT3, a key regulator in pro-tumoral macrophages, significantly reduced macrophage polarization in patients with malignant glioma.…”

Collagen Density Modulates the Immunosuppressive Functions of Tumor-Associated Macrophages

“…Therapeutic approaches aiming at re-programming TAMs toward a more pro-inflammatory phenotype have already been tested in mice 29,30 . These have shown promising results in various cancers, and have stimulated the initiation of clinical trials 31 . However, the molecular reason why TAMs gain an immunosuppressive phenotype in the TME is still not completely understood.…”