Interferon-γ–Dependent Infiltration of Human T Cells into Neuroblastoma Tumors In vivo

Purpose: To investigate the impact of interferon-γ–mediated upregulation of major histocompatibility complex class I expression on tumor-specific T-cell cytotoxicity and T-cell trafficking into neuroblastoma tumors in vivo . Experimental Design: Restoration of major histocompatibility complex class I expression by interferon-γ treatment enhances killing of neuroblastoma cells. To understand the potential of this approach in vivo , we developed a novel model of neuroblastoma in which NOD/ scid / IL2Rγ null immunodeficient mice are engrafted with both human T cells and tumor cells. Results: Here, we show enhanced killing of neuroblastoma cells by patient-derived, tumor-specific T cells in vitro . In addition, interferon-γ treatment in vivo induces efficient upregulation of major histocompatibility complex class I expression on neuroblastoma tumor cells, and this is accompanied by significantly enhanced infiltration of T cells into the tumor. In a pilot clinical trial in patients with high-risk neuroblastoma, we similarly observed augmented T-cell trafficking into neuroblastoma nests in tumor biopsy specimens obtained from patients after 5 days of systemic interferon-γ therapy. Conclusions: Interferon-γ overcomes critical obstacles to the killing of human neuroblastoma cells by specific T cells. Together, these findings provide a rationale for the further testing of interferon-γ as an approach for improving the efficacy of T cell–based therapies for neuroblastoma and other major histocompatibility complex class I–deficient malignancies. In addition, we describe a model that may expedite the preclinical screening of approaches aimed at augmenting T-cell trafficking into human tumors. (Clin Cancer Res 2009;15(21):6602–8)