Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity

Abstract

Tumor antigen (TA)-targeted monoclonal antibodies (mAb), trastuzumab, cetuximab, panitumumab, and rituximab, have been among the most successful new therapies in the present generation. Clinical activity is observed as a single agent, or in combination with radiotherapy or chemotherapy, against metastatic colorectal cancer, head and neck cancer, breast cancer, and follicular lymphoma. However, the activity is seen only in a minority of patients. Thus, an intense need exists to define the mechanism of action of these immunoactive mAb. Here, we discuss some of the likely immunological events that occur in treated patients: antibody-dependent cellular cytotoxicity (ADCC), cross talk among immune cells including NK cells and dendritic cells (DCs), and generation of TA-specific T lymphocyte responses. We present evidence supporting the induction of "NK:DC cross talk," leading to priming of TA-specific cellular immunity. These observations show that mAb-mediated NK cell activation can be greatly enhanced by the action of stimulatory cytokines and surface molecules on maturing DC and that NK:DC interaction facilitates the recruitment of both NK cells and DC to the tumor site(s). The cooperative, reciprocal stimulatory activity of both NK cells and DC can modulate both the innate immune response in the local tumor microenvironment and the adaptive immune response in secondary lymphoid organs. These events likely contribute to clinical activity, as well as provide a potential biomarker of response to mAb therapy.

Fig. 1

NK:DC cross talk promotes tumor antigen cross-presentation and T cell priming. An antitumor mAb (cetuximab) binds to TA (EGFR) on tumor cell surface, whereas Fc region of mAb binds to FcγR on immune cells (NK cells). This event activates NK cells leading to the lysis of tumor cells that generates TA and TA:mAb complex. The tumor antigenic materials are engulfed by immature DC and TA are processed and presented by mature DC to generate TA-specific T cells via MHCI through cross-presentation. Mature DC may furthermore activate NK cell reciprocally. Moreover, cytokines secreted by mAb-activated NK cells during ADCC may provide additional maturation inducing signals to DC

Fig. 2

NK:DC interaction enhances cetuximab-mediated activation of NK cells. Measurement of activated NK cells incubated with PCI-15B HNC or DC and PCI-15B HNC in the presence of control IgG1 mAb, panitumumab, or cetuximab (each 10 μg/ml) for 12 h by IFN-γ ELISPOT assay

Fig. 3

Cetuximab enhanced the cross-priming of EGFR-specific CTLs in the presence of NK cells. EGFR_853–861 antigen-specific CTLs were stimulated with DC (from HLA-A2⁺ healthy donor) fed with EGFR-positive, HLA-A2⁻ live PCI-15B HNC (Tu) either with cetuximab or isotype-matched control IgG1(each at 10 μg/ml), with or without autologous NK cells (DC:NK: PCI-15B;1:1:1 ratio) for 48 h. Afterward, DC was incubated with naïve CD8 T cells for 36 h, and the frequency of EGFR_853–861 antigen-specific CTLs activated under indicated conditions were examined for IFN-γ production by ELISPOT