| Abstract: |
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/IL2Rγnull 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. © 2009 American Association for Cancer Research. |
| Keywords: |
immunohistochemistry; human tissue; treatment outcome; treatment failure; clinical trial; nonhuman; cell proliferation; lymphocytes, tumor-infiltrating; animal cell; mouse; animals; mice; animal experiment; animal model; in vivo study; in vitro study; mice, scid; cell line, tumor; biopsy; engraftment; gamma interferon; neuroblastoma; pilot projects; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; histocompatibility antigens class i; cell migration; cytolysis; interferon-gamma; neoplasm transplantation; up-regulation; lymphocytic infiltration; mice, inbred nod; cell killing; gamma1b interferon; major histocompatibility antigen class 1
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