Self-antigen-specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response.
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% ( approximately 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.
Rizzuto
Gabrielle A
GA
Departments of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Merghoub
Taha
T
Hirschhorn-Cymerman
Daniel
D
Liu
Cailian
C
Lesokhin
Alexander M
AM
Sahawneh
Diana
D
Zhong
Hong
H
Panageas
Katherine S
KS
Perales
Miguel-Angel
MA
Altan-Bonnet
Grégoire
G
Wolchok
Jedd D
JD
Houghton
Alan N
AN