Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma

Abstract

Immune checkpoint inhibitors (ICIs) represent a promising therapeutic intervention for a variety of advanced/metastatic solid tumors, including melanoma, but in a large number of cases, patients fail to establish a sustained anti-tumor immunity and to achieve a long-lasting clinical benefit. Cells of the tumor micro-environment such as tumor-associated M2 macrophages (M2-TAMs) have been reported to limit the efficacy of immunotherapy, promoting tumor immune evasion and progression. Thus, strategies targeting M2-TAMs have been suggested to synergize with immune checkpoint blockade. This review recapitulates the molecular mechanisms by which M2-TAMs promote cancer immune evasion, with focus on the potential cross-talk between pharmacological interventions targeting M2-TAMs and ICIs for melanoma treatment.

Keywords: CTLA-4; PD-1; PD-L1; VEGFR-1; immune checkpoint; immune escape; macrophages; melanoma; metastasis.

Figure 1

Ontogeny of human tissue macrophages. Macrophages are a subtype of white blood cells, originating from bone marrow progenitors. Multipotent hematopoietic stem cells generate common myeloid progenitors, which in turn give rise to myeloblasts. Monocytes, derived from myeloblasts (which are also the precursors of basophils, neutrophils and eosinophils), are released from the bone marrow into the blood circulation, and, within a few days, they accumulate in various tissues throughout the body, representing a storage reservoir for the production of tissue macrophages. Resident tissue macrophages are also formed during the embryonic development, independently of blood monocytes. Tissue macrophages orchestrate their immune function by a polarization process towards two different phenotypes: M1, i.e., classically activated or inflammatory phenotype, and M2, i.e., alternatively activated or anti-inflammatory phenotype. See text for further details.

Figure 2

Mechanisms involved in the suppression of anti-tumor immunity mediated by TAMs. Immunosuppressive mechanisms supported by TAMs include: production of anti-inflammatory cytokines and chemokines and other inflammatory mediators that sustain Treg differentiation and hamper dendritic cell function; blockade of T-cell activation through the interaction with inhibitory immune checkpoints; depletion of essential metabolites for T-cell proliferation, such as arginine and tryptophan, due to the expression of specific metabolic enzymes (arginase-1, ARG-1, and indoleamine 2,3-dioxygenase, IDO, respectively); physical hindrance of T-cell recruitment in the TME. See text for further details.

Figure 3

Recent strategies aimed at targeting TAMs in combination with ICIs for melanoma treatment. The schematic drawing illustrates agents, evaluated in preclinical studies (brown) or clinical trials (blue) for melanoma treatment, acting through agonistic (green arrows or bracket) or antagonistic (red blunted arrows or brackets) mechanisms, in combination with anti-PD-1/PDL-1 or anti-CTLA-4 mAbs. GM-CSF agonists, CSF-1 antagonists and CSF1R inhibitors hamper a signaling pathway involved in M2-TAMs recruitment and polarization. IDO and ARG-1 inhibitors counteract depletion of tryptophan and arginine reservoir, respectively, both required for T-cell activity. The adenyl cyclase is a feasible target of anti-TAMs approaches since it inhibits TLR dependent pro-inflammatory NF-kB signaling, by increasing cAMP levels and promoting ICER expression. The same signaling pathway is negatively regulated by PI3K, thus justifying the experimental use of molecules targeting PI3K-γ. Consistently, another TAMs reprogramming pharmacological approach is represented by TLR agonists. Finally, the D16F7 mAb, directed against VEGFR-1, counteracts a signaling pathway involved in M2-TAMs chemotaxis and recruitment to the TME. See text for further details.