Interferon-gamma-dependent infiltration of human T cells into neuroblastoma tumors in vivo.
| Autor: | Reid GS; Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Shan X, Coughlin CM, Lassoued W, Pawel BR, Wexler LH, Thiele CJ, Tsokos M, Pinkus JL, Pinkus GS, Grupp SA, Vonderheide RH |
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| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2009 Nov 01; Vol. 15 (21), pp. 6602-8. Date of Electronic Publication: 2009 Oct 13. |
| DOI: | 10.1158/1078-0432.CCR-09-0829 |
| Abstrakt: | Purpose: To investigate the impact of interferon-gamma-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-gamma 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/IL2R gamma(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-gamma 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-gamma therapy. Conclusions: Interferon-gamma 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-gamma 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. |
| Databáze: | MEDLINE |
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