TY - JOUR
T1 - Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells
AU - Gattinoni, Luca
AU - Finkelstein, Steven E.
AU - Klebanoff, Christopher A.
AU - Antony, Paul A.
AU - Palmer, Douglas C.
AU - Spiess, Paul J.
AU - Hwang, Leroy N.
AU - Yu, Zhiya
AU - Wrzesinski, Claudia
AU - Heimann, David M.
AU - Surh, Charles D.
AU - Rosenberg, Steven A.
AU - Restifo, Nicholas P.
PY - 2005/10/3
Y1 - 2005/10/3
N2 - 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 γC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γC 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.
AB - 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 γC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γC 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.
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U2 - 10.1084/jem.20050732
DO - 10.1084/jem.20050732
M3 - Article
C2 - 16203864
AN - SCOPUS:25844484607
SN - 0022-1007
VL - 202
SP - 907
EP - 912
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -