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Immunosurveillance and Survivin-Specific T-Cell Immunity in Children With High-Risk Neuroblastoma

Christina M. Coughlin, Mark D. Fleming, Richard G. Carroll, Bruce R. Pawel, Michael D. Hogarty, Xiaochuan Shan, Barbara A. Vance, Jarish N. Cohen, Sonya Jairaj, Elaina M. Lord, Michael H. Wexler, Gwenn-aël H. Danet-Desnoyers, Jack L. Pinkus, Geraldine S. Pinkus, John M. Maris, Stephan A. Grupp, Robert H. Vonderheide

From the Abramson Family Cancer Research Institute; Hematology-Oncology Division, Department of Medicine; Department of Pathology and Laboratory Medicine; Division of Oncology, Department of Pediatrics; and Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Pathology, Children's Hospital; and the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Address reprint requests to Robert H. Vonderheide, MD, DPhil, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 551 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104; e-mail: rhv{at}mail.med.upenn.edu

PURPOSE: Tumor immunosurveillance influences oncogenesis and tumor growth, but it remains controversial whether clinical failure of immunosurveillance is a result of lymphocyte dysfunction or tumor escape. In this study, our goal was to characterize the physiology of tumor immunosurveillance in children with high-risk neuroblastoma (HR-NBL).

PATIENTS AND METHODS: Immunohistopathologic studies were carried out on 26 tumor samples from a cohort of HR-NBL patients diagnosed at Children's Hospital of Philadelphia for the 2-year period from May 2003 to May 2005. Blood from nine HLA-A2⁺ patients in this cohort was analyzed for T cells specific for the antiapoptotic protein survivin.

RESULTS: Survivin protein was expressed by 26 of 26 tumors. In HLA-A2⁺ patients, circulating cytotoxic T lymphocytes (CTLs) specific for survivin were detected by peptide/major histocompatibility complex tetramer analysis in the blood of eight of nine children with HR-NBL at the time of diagnosis. Rather than being selectively rendered anergic in vivo, circulating survivin-specific CTLs were highly functional as shown by cytotoxicity and interferon gamma enzyme-linked immunospot assays in six of nine patients. Survivin-specific CD107a mobilization by T cells was found in five of five patients. By immunohistochemistry, tumor-infiltrating T cells were few or absent in 26 of 26 tumors.

CONCLUSION: Children with HR-NBL harbor robust cellular immune responses to the universal tumor antigen survivin at the time of diagnosis, but intratumoral T cells are strikingly rare, suggesting a failure of cellular immunosurveillance. Efforts to develop novel therapies that increase T-cell trafficking into tumor nests are warranted.

Supported by National Cancer Institute Grants No. R21-CA110516 (S.A.G.) and R01 CA113783 (R.G.C.), and grants from Alex's Lemonade Stand (J.M.M.), the Damon Runyon Cancer Research Fund (R.H.V.), the Alliance for Cancer Gene Therapy (R.H.V.), and the Pennsylvania Department of Health (R.H.V.).

The Pennsylvania Department of Health specifically disclaims responsibility for any analysis, interpretations, or conclusions.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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