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Introduction: Most bispecific antibody (BsAb) therapies focus on stimulating the adaptive immune system, in particular T cells, to promote tumor cell killing. Another method to promote tumor eradication is through the engagement of myeloid cells, including macrophages and neutrophils, which are abundantly present and possess intrinsic cytotoxic mechanisms for tumor cell killing, making them interesting effector cells to recruit for BsAb therapy. Areas covered: In this review, we describe the evolving knowledge of the role of macrophages and neutrophils in cancer in scientific literature. Moreover, we address the BsAbs that have been developed over the years to recruit these cell types as effector cells in immunotherapy of cancer. This includes the discussion of BsAbs that target Fc receptors (i.e. FcγR and FcαRI) to induce antibody-dependent cellular phagocytosis (ADCP) by macrophages or trogoptosis via neutrophils, as well as BsAbs that interfere with checkpoint inhibition, including the SIRPα-CD47 pathway. Expert opinion: Elucidating the complexity of macrophage and neutrophil heterogeneity in cancer may help to specifically enlist the cytotoxic ability of these cells through targeting Fc receptors and checkpoint pathways, which may further enhance anti-cancer immunity.

In the past 25 years, a considerable number of therapeutic monoclonal antibodies (mAb) against a variety of tumor-associated antigens (TAA) have become available for the targeted treatment of hematologic and solid cancers. Such antibodies opsonize cancer cells and can trigger cytotoxic responses mediated by Fc-receptor expressing immune cells in the tumor microenvironment (TME). Although frequently ignored, neutrophils, which are abundantly present in the circulation and many cancers, have demonstrated to constitute bona fide effector cells for antibody-mediated tumor elimination in vivo. It has now also been established that neutrophils exert a unique mechanism of cytotoxicity towards antibody-opsonized tumor cells, known as trogoptosis, which involves Fc-receptor (FcR)-mediated trogocytosis of cancer cell plasma membrane leading to a lytic/necrotic type of cell death. However, neutrophils prominently express the myeloid inhibitory receptor SIRPα, which upon interaction with the ‘don’t eat me’ signal CD47 on cancer cells, limits cytotoxicity, forming a mechanism of resistance towards anti-cancer antibody therapeutics. In fact, tumor cells often overexpress CD47, thereby even more strongly restricting neutrophil-mediated tumor killing. Blocking the CD47-SIRPα interaction may therefore potentiate neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) towards cancer cells, and various inhibitors of the CD47-SIRPα axis are now in clinical studies. Here, we review the role of neutrophils in antibody therapy in cancer and their regulation by the CD47-SIRPα innate immune checkpoint. Moreover, initial results of CD47-SIRPα blockade in clinical trials are discussed.

Tumor-targeting monoclonal antibodies are available for a number of cancer cell types (over)expressing the corresponding tumor antigens. Such antibodies can limit tumor progression by different mechanisms, including direct growth inhibition and immune-mediated mechanisms, in particular complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and antibody-dependent cellular cytotoxicity (ADCC). ADCC can be mediated by various types of immune cells, including neutrophils, the most abundant leukocyte in circulation. Neutrophils express a number of Fc receptors, including Fcγ- and Fcα-receptors, and can therefore kill tumor cells opsonized with either IgG or IgA antibodies. In recent years, important insights have been obtained with respect to the mechanism(s) by which neutrophils engage and kill antibody-opsonized cancer cells and these findings are reviewed here. In addition, we consider a number of additional ways in which neutrophils may affect cancer progression, in particular by regulating adaptive anti-cancer immunity.