Abstract
Current tumor therapies, including immunotherapies, focus on passive eradication or at least reduction of the tumor mass. However, cancer patients quite often suffer from tumor relapse or metastasis after such treatments. To overcome these problems, we have developed a natural killer T (NKT) cell-targeted immunotherapy focusing on active engagement of the patient’s immune system, but not directly targeting the tumor cells themselves. NKT cells express an invariant antigen receptor α chain encoded by Trav11 (Vα14)-Traj18 (Jα18) gene segments in mice and TRAV10 (Vα24)-TRAJ18 (Jα18) in humans and recognize glycolipid ligand in conjunction with a monomorphic CD1d molecule. The NKT cells play a pivotal role in the orchestration of antitumor immune responses by mediating adjuvant effects that activate various antitumor effector cells of both innate and adaptive immune systems and also aid in establishing a long-term memory response. Here, we established NKT cell-targeted therapy using a newly discovered NKT cell glycolipid ligand, RK, which has a stronger capacity to stimulate both human and mouse NKT cells compared to previous NKT cell ligand. Moreover, RK mediates strong adjuvant effects in activating various effector cell types and establishes long-term memory responses, resulting in the continuous attack on the tumor that confers long-lasting and potent antitumor effects. Since the NKT cell ligand presented by the monomorphic CD1d can be used for all humans irrespective of HLA types, and also because NKT cell-targeted therapy does not directly target tumor cells, this therapy can potentially be applied to all cancer patients and any tumor types.
Highlights
Immunotherapy, which acts by harnessing the power of patient’s own immune system, has recently emerged as a treatment option to combat cancer in addition to conventional treatment options such as surgery, chemotherapy, and radiation therapy [1]
We demonstrate that RK-pulsed dendritic cells (DCs) have remarkable potential for induction of natural killer T (NKT) cell-mediated adjuvant activity by activating downstream cell types such as NK and CD8 T cells, and in the establishment of long-term memory responses against a model antigen ovalbumin
For the initial screening assay to measure the NKT cell activating potential of the newly synthesized compounds, we used a cell-free antigen presentation assay, in which soluble CD1d was coated on a culture plate, pulsed with glycolipid antigens, and IFN-γ release from the NKT cell hybridoma 2E10 expressing an invariant Vα14Jα18 TCRα paired with Vβ8 was used as a readout [25]
Summary
Immunotherapy, which acts by harnessing the power of patient’s own immune system, has recently emerged as a treatment option to combat cancer in addition to conventional treatment options such as surgery, chemotherapy, and radiation therapy [1]. Tumor relapse and metastasis still remain a major problem for any of the current anticancer therapies. A common and significant limitation of current anticancer immunotherapies is that they often target only one type of antitumor effector cell. In the immunotherapy approaches using tumor peptide-specific CTL, dendritic cells (DCs), engineered CAR-T cells, tumor-infiltrating lymphocytes, or antibodies against PD-1, the target is the effector T cell, which kills MHC-positive, but not MHC-negative, tumor cells, resulting in recurrence of MHC-negative tumor cells [2]. In the case of lymphokine-activated NK cells or NK cells generated by the enforced expression of NK receptor ligands, such as Rae1/ H60/Mult-1 (NKG2D-L), the effector cells eliminate only MHC-negative tumor cells, resulting in the relapse by MHCpositive tumor cells [3]. Tumor cells often undergo mutational changes that render them resistant to these therapies
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