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Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11476-81.

In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance.

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Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.


The efficacy of therapeutic vaccination for the treatment of cancer is limited by peripheral tolerance to tumor antigens. In vivo blockade of CTLA-4, a negative regulator of T cell function, can induce the regression of established tumors and can augment the tumor rejection achieved through therapeutic vaccination. These outcomes may reflect enhanced tumor-specific T cell priming and/or interference with the development of tolerance to tumor antigens. We examined the effect of CTLA-4 blockade on the fate and function of T cells specific for a model tumor antigen in the tumor-bearing host. We found that while CTLA-4 blockade enhanced the priming of responsive T cells, it did not prevent the induction of tolerance to tumor antigens. These results demonstrate that there is a critical window in which the combination of CTLA-4 blockade and vaccination achieves an optimal response, and they point to mechanisms other than CTLA-4 engagement in mediating peripheral T cell tolerance to tumor antigens.

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