Osteosarcoma (OS) is the most common primary malignant bone tumor in children. Pulmonary metastasis is the major cause of mortality in OS patients with a 25-30 % 5-year survival rate. Therefore, development of novel targeted approaches like immunotherapy has been the interest of investigators.

Previously, we have demonstrated that Liposomal muramyl tripeptipe phosphatidyl ethanolamine (L-MTP-PE) reduced the metastatic burden in animal models and caused an 8% improvement in the overall survival of patients with OS metastatic disease through macrophage activation. The adoptive transfer of mature natural killer (NK) cells activated ex vivo has exhibited anti-tumor efficacy in breast cancer and lymphoma models. It has been shown that NK cells exert cytotoxicity against OS cells in vitro. Aerosolized interleukin 2 (IL-2) administered to dogs with OS lung disease has demonstrated therapeutic benefit. Additionally, Guma S. R. et al. showed that aerosol IL-2 enhanced the efficacy of infused NK cells against OS lung metastasis in vivo. Aerosol IL-2 and NK cell combination therapy resulted in the regression of OS lung metastasis through enhanced tumor cell apoptosis. Moreover, the combination therapy significantly increased the overall survival of mice with OS lung metastases. However, the treatment is not curative as metastasis persists leading to relapse. Recent studies have demonstrated the immunosuppressive role of checkpoint inhibitors such as programmed death receptor 1 (PD-1) and its ligand, programmed death ligand 1 (PDL-1). Inhibition of the PD-1/PDL-1 pathway has shown immunotherapeutic benefit in lung and renal tumors. Involvement of this pathway in OS lung metastases is unknown. Therefore, based on our previous studies of aerosol IL-2, we hypothesize that aerosol IL-2 causes upregulation of PDL-1 expression on OS tumor cells, which in turn interacts with PD-1 receptor on NK cells, restricting NK cells' killing ability against OS. Our preliminary data demonstrates high PDL-1 expression in human OS cells and OS lung metastases from patients. Using a human OS mouse model, we further show that aerosol IL-2 enhances PDL-1 expression in OS lung metastases. PDL-1 expression on OS lung nodules was observed towards the tumor periphery. Hence, we propose that targeting the PD-1/ PDL-1 axis using anti-PD-1 antibody will enhance the efficacy of NK cell-directed therapy, in the presence or absence of IL-2, against OS lung metastasis and improve the overall survival.

Citation Format: Pooja M. Dhupkar, Eugenie Kleinerman, Nancy Gordon. Immune modulation of natural killer cell adoptive transfer for the treatment of Osteosarcoma lung metastastasis: Targeting the PD-1/ PDL-1 signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A65.