Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

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.

The Association between a Decrease in On-Treatment Neutrophil-to-Eosinophil Ratio (NER) at Week 6 after Ipilimumab Plus Nivolumab Initiation and Improved Clinical Outcomes in Metastatic Renal Cell Carcinoma

“…The search for biomarkers has led to enhanced understanding of the tumor microenvironment (TME) in IO-treated patients [ 8 , 9 ]: studies have elucidated the complex interactions between infiltrating immune cells, tumor cells, and other surrounding cell, such as fibroblasts and endothelial cells [ 9 , 10 ]. While infiltrating T lymphocytes caught the early attention of researchers in the studies of TME [ 11 ], there has been rapidly accumulating evidence supporting the roles of myeloid cells [ 12 , 13 ] in the response of ICIs, such as the myeloid-derived suppressor cells and tumor-associated macrophages [ 14 ]. Furthermore, there is growing evidence among pre-clinical studies suggesting that eosinophils are essential cells in the TME for the anti-tumor activity observed with IO [ 15 , 16 ].…”

Tumor microenvironment-related multigene prognostic prediction model for breast cancer

“…Mononuclear cells are precursors of tumor-associated macrophages (TAMs) which comprise the most abundant proportion of tumor-infiltrating immune cells [ 40 ]. Substantial evidence showed that TAMs are highly associated with poor prognosis in cancer [ 41 , 42 ]. The potential mechanism of TAMs is complicated and includes tumor promotion, an increase in cancer resistance, and promotion of cancer cell migration [ 43 – 46 ].…”

Lysine Acetylation/Deacetylation Modification of Immune-Related Molecules in Cancer Immunotherapy

“…Therapeutic antibodies are laboratory-made antibodies designed to destroy tumor cells in different ways, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct induction of apoptosis by antibodies ( 133 ). Several therapeutic antibodies have been approved for the clinical treatment of cancer.…”