Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

SIMPLE SUMMARY: In addition to cancer cells themselves, tumors consist of several cell types that either function to suppress or promote tumor growth and disease progression. Macrophages are amongst the most abundant of these cell types and possess contrasting abilities to either enhance tumor growth and spread or to destroy cancer cells. Anti-cancer therapeutics such as Rituximab, Herceptin and Cetuximab, are cornerstones of current treatment for cancer patients. These therapeutics are antibodies that directly bind to cancer cells and aid macrophages in detecting and destroying these cells, through a process known as antibody dependent cellular phagocytosis (ADCP). Although the use of anti-cancer antibodies to treat large established tumors has improved survival rates, significant numbers of patients do not respond to this type of therapy. Thus, recently there has been an intense focus on designing new therapies which alter macrophages inside tumors, so that they can more effectively eliminate cancer cells through ADCP. Several molecules on the surface of macrophages can be targeted with antibodies to improve their ability to recognize and eliminate cancer cells. Here we review the most promising of these new targets, which offer the potential to circumvent resistance to therapy in cancer patients. ABSTRACT: Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called ‘phagocytosis checkpoints’. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of ‘don’t eat me signals’ or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance.