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¹ Departments of Medicine and Immunology, ² Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
³ Weill School of Medicine of Cornell University, New York, NY 10065

CORRESPONDENCE Alan N. Houghton: houghtoa{at}mskcc.org OR Jedd D. Wolchok: wolchokj{at}mskcc.org

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-specific cells increased vaccine-elicited tumor immunity and autoimmunity, but a threshold was reached whereby the transfer of increased numbers of antigen-specific cells impaired functional benefit, 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-specific 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 efficacy of clinical vaccine strategies designed to activate any antigen-specific CD8⁺ T cells.

Abbreviation used: DLN, draining LN.

© 2009 Rizzuto et al.
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This article has been cited by other articles:

• Seedhom, M. O., Jellison, E. R., Daniels, K. A., Welsh, R. M. (2009). High Frequencies of Virus-Specific CD8+ T-Cell Precursors. J. Virol. 83: 12907-12916 [Abstract] [Full Text]  

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