Fig. 2. Mechanisms of action of antibody-based immunotherapy in cancer.

Mechanisms of antitumor antibody therapies are distinct and based on the antibody structure and function. Displayed are various strategies for antibody mediated tumor death. Upper left: direct cytotoxicity, in which mAbs induce cytotoxicity directly to the tumors by trumping signaling pathways or in which immune-conjugates kill targeted cells. Lower left: FcReceptor-mediated immune effector engagement, in which the Fc portion of mAbs engage immune effector functions, including soluble CMC (through the membrane attack complex MAC) as well as NK cells, macrophages, and dendritic cells, through FcRs, allowing for ADCC, ADCP, and IC uptake. Upper right: Non-restricted activation of cytotoxic T cells, in which tumor-infiltrating CTLs can be activated against tumor cells—independent of T cell receptor (TCR) specificity—by engaging co-receptors on the T cells and tumor antigens. Lower right: blockade of inhibitory signaling, in which cytotoxic lymphocytes, including NK cells and CTLs, express inhibitory receptors for various ligands (such as PD-L1) that may be expressed by tumor cells. Antagonistic antibodies that target these inhibitory receptors can block ligand-receptor interactions so that targeted cytotoxicity can ensue (such as the FDA approved CTLA-4 and PD-1 blocking antibodies). These four strategies enhance tumor cell death, which can promote phagocytosis of tumor cell antigens, and induction of adaptive immune responses (bottom right) in two ways: MHC class I cross-presentation and priming of cytotoxic T cells and MHC class II presentation and priming of helper T cells. These adaptive immune responses can enhance antitumor immunity. Figure reprinted from Cell, Volume 128, pages 1081-1084, Weiner LM, Murray JC, Shuptrine CW, 'Antibody-based immunotherapy of cancer'. Copyright 2012, with permission from Elsevier (38).