Immunosurveillance and survivin-specific T-cell immunity in children with high-risk neuroblastoma.
OBJECTIVE
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).


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.


CONCLUSIONS
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.
Coughlin
Christina M
CM
Abramson Family Cancer Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Fleming
Mark D
MD
Carroll
Richard G
RG
Pawel
Bruce R
BR
Hogarty
Michael D
MD
Shan
Xiaochuan
X
Vance
Barbara A
BA
Cohen
Jarish N
JN
Jairaj
Sonya
S
Lord
Elaina M
EM
Wexler
Michael H
MH
Danet-Desnoyers
Gwenn-aël H
GA
Pinkus
Jack L
JL
Pinkus
Geraldine S
GS
Maris
John M
JM
Grupp
Stephan A
SA
Vonderheide
Robert H
RH
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007157:Immunologic Surveillance; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000276:immunology*; D012307:Risk Factors; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin