Self-antigen-specifc CD8(+) T cell precursor frequency determines the quality of the antitumor immune response Journal Article

Authors: Rizzuto, G. A.; Merghoub, T.; Hirschhorn-Cymerman, D.; Liu, C.; Lesokhin, A. M.; Sahawneh, D.; Zhong, H.; Panageas, K. S.; Perales, M. A.; Altan-Bonnet, G.; Wolchok, J. D.; Houghton, A. N.
Article Title: Self-antigen-specifc CD8(+) T cell precursor frequency determines the quality of the antitumor immune response
Abstract: A primary goal of cancer immunotherapy is to improve the naturally occurring, but weak, immune response to tumors. Ineffective responses to cancer vaccines may be caused, in part, by low numbers of self-reactive lymphocytes surviving negative selection. Here, we estimated the frequency of CD8 (+) T cells recognizing a self-antigen to be <0.0001% (∼1 in 1 million CD8(+) T cells), which is so low as to preclude a strong immune response in some mice. Supplementing this repertoire with naive antigen-specifc cells increased vaccineelicited tumor immunity and autoimmunity, but a threshold was reached whereby the transfer of increased numbers of antigen-specifc cells impaired functional beneft, most likely because of intraclonal competition in the irradiated host. We show that cells primed at precursor frequencies below this competitive threshold proliferate more, acquire polyfunctionality, and eradicate tumors more effectively. This work demonstrates the functional relevance of CD8(+) T cell precursor frequency to tumor immunity and autoimmunity. Transferring optimized numbers of naive tumor-specifc T cells, followed by in vivo activation, is a new approach that can be applied to human cancer immunotherapy. Further, precursor frequency as an isolated variable can be exploited to augment effcacy of clinical vaccine strategies designed to activate any antigen-specifc CD8(+) T cells. © 2009 Rizzuto et al.
Keywords: nonhuman; antineoplastic agent; neoplasm; neoplasms; cd8 antigen; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; animals; mice; cell division; melanoma; spleen; skin neoplasms; in vivo study; pathology; radiation exposure; skin tumor; immunology; immune response; immunotherapy; pre t lymphocyte; vaccination; experimental melanoma; melanoma, experimental; autoantigen; autoantigens; tumor immunity; autoimmunity; lymphocyte antigen receptor; receptors, antigen, t-cell, alpha-beta; antigens, cd8
Journal Title: Journal of Experimental Medicine
Volume: 206
Issue: 4
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2009-04-13
Start Page: 849
End Page: 866
Language: English
DOI: 10.1084/jem.20081382
PUBMED: 19332877
PROVIDER: scopus
PMCID: PMC2715122
Notes: --- - "Cited By (since 1996): 17" - "Export Date: 30 November 2010" - "CODEN: JEMEA" - "Source: Scopus"
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