Targeting a scavenger receptor on tumor-associated macrophages activates tumor cell killing by natural killer cells

Significance Here we report that targeting the pattern recognition receptor MARCO on macrophages within the tumor alters their polarization and in turn activate natural killer (NK) cells to kill the tumor. We describe the mechanism of action, including that NK cells are induced to use receptor-mediated killing of the cancer cells. Furthermore, we find that this type of treatment works in combination with T cell-targeted checkpoint therapies. We then transfer this finding to humans and find that similar subpopulations of human macrophages also block NK cells. Finally, we find that targeting these human macrophages with a new specific antibody that we generated can activate these to release NK cell killing, thus generating a venue for combinatory treatments for cancer. Tumor-associated macrophages (TAMs) can have protumor properties, including suppressing immune responses, promoting vascularization and, consequently, augmenting tumor progression. To stop TAM-mediated immunosuppression, we use a novel treatment by injecting antibodies specific for scavenger receptor MARCO, which is expressed on a specific subpopulation of TAMs in the tumor. We now report the location of this TAM as well as the pleiotropic mechanism of action of anti-MARCO antibody treatment on tumor progression and further show that this is potentially relevant to humans. Using specific targeting, we observed decreased tumor vascularization, a switch in the metabolic program of MARCO-expressing macrophages, and activation of natural killer (NK) cell killing through TNF-related apoptosis-inducing ligand (TRAIL). This latter activity reverses the effect of melanoma cell-conditioned macrophages in blocking NK activation and synergizes with T cell-directed immunotherapy, such as antibodies to PD-1 or PD-L1, to enhance tumor killing. Our study thus reveals an approach to targeting the immunosuppressive tumor microenvironment with monoclonal antibodies to enhance NK cell activation and NK cell-mediated killing. This can complement existing T cell-directed immunotherapy, providing a promising approach to combinatorial immunotherapy for cancer.