The Journal of Experimental Medicine
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Published 3 October 2005. doi:10.1084/jem.20050732
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 7, 907-912
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BRIEF DEFINITIVE REPORT

 Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells

Luca Gattinoni1, Steven E. Finkelstein1, Christopher A. Klebanoff1,2, Paul A. Antony1, Douglas C. Palmer1, Paul J. Spiess1, Leroy N. Hwang1, Zhiya Yu1, Claudia Wrzesinski1, David M. Heimann1, Charles D. Surh3, Steven A. Rosenberg1, and Nicholas P. Restifo1

1 Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
2 Howard Hughes Medical Institute, NIH Research Scholars Program, Bethesda, MD 20814
3 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

CORRESPONDENCE Nicholas P. Restifo: restifo{at}nih.gov

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The {gamma}C cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of {gamma}C cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

L. Gattinoni, S.E. Finkelstein, and C.A. Klebanoff contributed equally to this work.


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