Cancer Immunotherapy Using Tumor Opsonization

Although tumor antigen-specific immunotherapy, such as dendritic cell vaccine, has recently emerged as a promising clinical approach, one limitation of tumor antigenand T-cell receptor (TcR)specific immunotherapy is antigenspecific inhibition by antigen-specific regulatory T-cell and myeloid suppressor cells. Therefore, immunotherapy using a TcR-independent mechanism may be an alternative immunotherapeutic strategy. NKG2D (natural killer, group 2, member D) and DNAX accessory molecule-1 (DNAM-1) are both activated receptors that are strongly expressed on T-cells, γδT-cells, and NK cells. Therefore, the expression of ligands for NKG2D and DNAM-1 on tumor cells plays an important role in tumor opsonization by immune effector cell targeting. Various modulatory methods for up-regulating NKG2D and DNAM-1-ligands have been reported, and included chemotherapeutic agents and hyperthermia. Although there are many obstacles to the utilization of NKG2D and DNAM-1 for cancer therapy, combined treatments using immune cell therapy and chemotherapy that take advantage of NKG2D and DNAM-1 may be an ideal approach. Cancer Immunotherapy Using Tumor Opsonization Cancer immunotherapy aims to activate the immune system for cancer eradication. After a disappointingdly long time, the tide has at last changed due to an understanding of the mechanisms of tumor immunity and success of recent clinical trials (1, 2). Cancer immunotherapy consists of T-cell receptor (TcR)-dependent and -independent mechanisms. Although tumor antigen-specific and TcR-dependent immunotherapy is an ideal immunotherapy, there are many limitations, such as tumor antigen-specific inhibitory mechanisms exerted by regulatory T-cell and myeloid-derived suppressor cells (3-5). Moreover, it is unknown which antigens can be effectively targeted by immune cells for many types of cancer. Alternatively, a biologically therapeutic strategy is to sensitize or opsonize tumor cells and trigger their death using immune cytotoxic effector cells such as activated natural killer (NK) cells and T cells. Recently there have been many studies reporting the clinical effects of nonspecific cytokine-activated T-cells and NK cells. However, cell therapy alone has not achieved sufficiently effective clinical results (6, 7). In this review, we examine the possibility of combining tumor opsonization methods and immune cell therapy focusing on the natural killer, group 2, member D (NKG2D) and DNAX accessory molecule-1 (DNAM-1) systems, and discuss future perspectives on the combination of chemotherapy and immune cell therapy. NKG2D and its Ligands NKG2D is a potent activating receptor expressed on virtually all NK cells, γδT-cells, and CD8 T-cells, and the interaction of NKG2D with its ligands in the tumors plays an important role in the immune response to tumors (8-12). NKG2D is a C-type lectin-like receptor expressed on cell surface and has been classified as a killer cell lectin receptor of superfamily K, member 1 (KLRK1), which is encoded by the Nkg2d (Klrk1) gene that is located within the NK gene complex (NKC) situated on chromosome 12 in humans (10-12). NKG2D is a homodimer and recognizes a number of stress induced MHC class I-like ligands. The ligands are summarized and shown in Figure 1. In humans, NKG2D binds to the MHC class I-related proteins MICA and MICB (MHC class I chain-related protein A and B), UL-16 binding proteins (ULBPs). There are six members of the ULBP family of proteins, which are closely related to Rae1 molecules in mice. ULBP1, -2, and -3 and -6 are GPI2241 Corresponence to: Dr. Takashi Morisaki, Fukuoka General Cancer Clinic, 3-1-1 Sumiyoshi, Hakata-ku, Fukuoka 812-0018, Japan. Tel: +81 922827696, Fax: +81 924056376, e-mail: [email protected]