The therapeutic efficacy of some anti-tumor monoclonal antibodies (mAbs) depends on the capacity of the mAb to recognize the tumor-associated antigen and induce cytotoxicity via a network of immune effector cells. review, we discuss strategies for enhancing ADCC and emphasize the potential of combination treatments that include US Food and Drug Administration-approved mAbs and immunostimulatory therapeutics. (TLR2/TLR4), monophosphoryl lipid A (TLR4), and imiquimod (TLR7).80,81 However, recent in vitro studies have demonstrated that TLR8 stimulation through its agonist VTX-2337 enhanced the activation and function of NK cells in the presence of cetuximab-coated head and neck cancer cells.82 Similarly the TLR3 ligand polyinosinic:polycytidylic acid (polyI:C) increased the cetuximab-dependent ADCC by NK cells against head and neck malignancy cell lines. During cetuximab-induced ADCC, the percentage of activated NK cells (CD107a+granzyme W+) increased significantly in presence of both the agonist and cetuximab, compared to either of them alone.83 Thus these TLR agonists in combination with cetuximab can enhance cetuximab induced ADCC against head and neck cancer. In another study involving TLR9, it has been exhibited that CpG-containing oligodeoxynucleotides (CpG ODN), the TLR9 agonist, can directly promote the secretion of cytokines by NK cells uncovered to antibody-coated tumor cells by activating TLR9.84 Further, Sommariva et al85 have demonstrated in an in vivo advanced ovarian xenograft model that mice treated with a combination of CpG ODN and cetuximab had a significantly increased median survival rate relative to monotherapy with either agent. CpG ODNs can also activate NK cells through indirect activation of plasmacytoid DCs that stimulate IFN- production by T cells.86 CpG ODNs can also induce CD20 manifestation on malignant B cells.87 Thus the activating effect of CpG ODN on the effector cells as well as on the tumor cells can have a synergistic effect when used in combination with mAbs. It has been shown in preclinical studies that CpG ODNs enhance antitumor activity of rituximab in treating lymphomas88,89 and trastuzumab in treating breast malignancy.87,90 Effector cell activation: agonistic and antagonistic mAbs The 1213269-98-7 importance of utilizing mAb therapy to elicit ADCC-mediated tumor clearance was initially established by studies exploring the mechanism of action of rituximab. One of the primary mechanisms by which rituximab exerts its antitumor effects is usually by making the CD20-conveying tumor a more attractive target for NK cell lysis. In the decades following the introduction 1213269-98-7 Rho12 of rituximab, subsequent mAbs have been developed that augment ADCC. A particularly promising strategy for enhancing ADCC via mAb therapy is usually targeting the costimulatory pathways that activate NK cell cytotoxicity. One molecule that has exhibited strong preclinical success in this approach is usually CD137. CD137 CD137 is usually a member of TNF receptor superfamily and is usually upregulated on NK 1213269-98-7 cells after FcRIIIa (CD16) ligation.91 Administration of agonistic anti-CD137 mAbs has been shown to amplify antitumor immune responses in a variety of different murine cancer models.92 On NK cells, activation of CD137 increases proliferation, degranulation, and IFN- secretion, leading to enhanced ADCC.93 The ability of anti-CD137 mAbs to enhance ADCC makes them ideal candidates for combination therapeutic strategies. We have previously exhibited that targeting CD137 concomitantly with rituximab or trastuzumab administration accelerates tumor clearance in murine xenograft models of lymphoma and breast malignancy.94,95 Recently, we combined cetuximab and anti-CD137 antibody therapy to obtain complete tumor resolution and prolonged survival in xenograft models of epidermal growth factor receptor-expressing cancer cells, head and neck cancer cells, and wild-type Kirsten rat sarcoma 2 viral oncogene homolog (KRAS-WT) and KRAS-mutant colorectal cancer.96 An anti-CD137 antibody, urelumab, is currently in clinical trials with rituximab for patients with non-Hodgkins lymphoma (“type”:”clinical-trial”,”attrs”:”text”:”NCT01775631″,”term_id”:”NCT01775631″NCT01775631) and with cetuximab in patients with colorectal cancer or head and neck cancer (“type”:”clinical-trial”,”attrs”:”text”:”NCT02110082″,”term_id”:”NCT02110082″NCT02110082). KIR signaling The killer cell immunoglobulin-like receptor (KIR) family constitutes one of the key mediators of NK cell activation. Inhibitory KIR molecules hole to the self-major histocompatibility complex class I ligands (HLA-A, HLA-B, HLA-C) and upon binding transduce inhibitory signals that abrogate the effects of 1213269-98-7 activating receptors.97 Because major histocompatibility complex class I is expressed on virtually all healthy cells, KIR molecules are considered to be one of the primary mechanisms responsible for NK cell tolerance to self. Reducing KIR-mediated inhibitory signaling in NK cells via antibody blockade has been shown to increase NK cell cytotoxicity and survival of leukemia-bearing mice.98 A fully human mAb that binds KIR2DL1, KIR2DL2, and KIR2DL3 receptors enhanced NK cell-mediated.