Macrophages are innate immune cells that derive from circulating monocytes, reside in all tissues, and participate in many states of pathology. Macrophages play a dichotomous role in cancer, where they promote tumor growth but also serve as critical immune effectors of therapeutic antibodies. Macrophages express all classes of Fcγ receptors, and they have immense potential to destroy tumors via the process of antibody-dependent phagocytosis. A number of studies have demonstrated that macrophage phagocytosis is a major mechanism of action of many antibodies approved to treat cancer. Consequently, a number of approaches to augment macrophage responses to therapeutic antibodies are under investigation, including the exploration of new targets and development of antibodies with enhanced functions. For example, the interaction of CD47 with signal-regulatory protein α (SIRPα) serves as a myeloid-specific immune checkpoint that limits the response of macrophages to antibody therapies, and CD47-blocking agents overcome this barrier to augment phagocytosis. The response of macrophages to antibody therapies can also be enhanced with engineered Fc variants, bispecific antibodies, or antibody-drug conjugates. Macrophages have demonstrated success as effectors of cancer immunotherapy, and further investigation will unlock their full potential for the benefit of patients.
Keywords: ADC, antibody-drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP; ADCP, antibody-dependent cellular phagocytosis; AML, acute myelogenous leukemia; BTK, Bruton's tyrosine kinase; CD, cluster of differentiation; CD47; CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; Fc receptor; Fc, fragment crystallizable; FcγR, Fcγ receptors; GM-CSF, granulocyte-macrophage colony stimulating factor; HER2, human epidermal growth factor receptor 2; HSC, haematopoietic stem cell; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; IgG, immunoglobulin G; M-CSF, macrophage colony stimulating factor; NK, natural killer; SHP, Src homology 2 domain-containing phosphatase; SIRPα; SIRPα, signal-regulatory protein α; antibodies; cancer; immune checkpoint; immunotherapy; macrophages; phagocytosis.