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Comment on "Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade"

Metabolism Branch, National Cancer Institute, Bethesda, MD 20892

In the December 1, 2005, issue of The Journal of Immunology, Maker et al. (1) conclude that the effects of CTLA-4 blockade are due to increased T cell activation rather than inhibition or depletion of T regulatory cells. The authors examined the effects of anti-CTLA-4 administration on T regulatory cells before and at 3 wk after each dose. They saw no reduction in CD4⁺CD25⁺ T cells, and to characterize further the T regulatory cell population, they examined Foxp3 gene expression. Increased Foxp3 expression was observed at 3 wk posttreatment compared with pretreatment levels in purified CD4⁺CD25⁺cells. We believe their conclusion that T regulatory cell depletion is not involved in the mechanism of action of anti-CTLA-4 is flawed by a failure to examine its effect at early time points after administration. We postulated that expression of CTLA-4 on T regulatory cells targeted them for Ab-dependent cytotoxicity. PBMCs from patients with advanced malignancy were examined before, within 1–4 days, and 3–4 wk after anti-CTLA-4 administration. At 1–4 days after administration, there was a significant decrease in the number of T regulatory cells as quantitated by expression of CD4, CD25, and CD62L. However, at the time of administration of the next dose, the number of T regulatory cells had increased above baseline, in agreement with the results of Maker et al. These results were confirmed by TaqMan analysis for Foxp3 expression; a decrease at early times was followed by a rebound increase by the next treatment. This depletion followed by increased levels of Foxp3 assayed by TaqMan mirrored the results from flow cytometry. The dynamic changes in T regulatory cells was missed in Maker’s analysis by restricting data collection time points. We agree, but have been unable to demonstrate, that increased T cell activation is responsible for the antitumor effects of anti-CTLA-4 but believe that transient depletion of T regulatory cells permits activation of T cells that recognize self Ags, which in turn produce autoimmunity and tumor regression.

This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

References

1. Maker, A. V., P. Attia, S. A. Rosenberg. 2005. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J. Immunol. 175: 7746-7754. [Abstract/Free Full Text]

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