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Does CTLA4 Influence the Suppressive Effect of CD25+CD4+ Regulatory T Cells?

Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy

To the Editor:

Beck et al¹ have recently reported that one of the potential mechanisms for generating enterocolitis after anti-CTLA4 antibody involves CD25+CD4+ regulatory T cells (Treg). It has been hypothesized that anti-CTLA4 antibody might deplete Treg cells, inducing autoimmunity. However, patients receiving ipilimumab have not shown a decrease in Treg number or function in peripheral blood.² It should be emphasized that the measurements of Treg function reported in this study² were performed on circulating lymphocytes and not specifically on lymphocytes with antitumor activity. Unfortunately, the low levels of antitumor T cells in these patients precluded the authors' ability to measure HLA-DR expression, a T-cell activation marker, specifically on these cells.

Treg are the only CD4+ cells in the naive mouse that express the CTLA4 Ag. It has been demonstrated that anti-CTLA4 antibody was capable of abrogating Treg-mediated suppression in vitro and that treatment of normal adult mice with anti-CTLA4 antibody induced gastritis.³ In a colitis mouse model, the suppressive effect of Treg was abolished by anti-CTLA4 antibody,⁴ consistent with the important role of CTLA4 Ag in autoimmune diseases in vivo. Conversely, the suppressive effect of CD25+CD4+ T cells on CD25+CD4- T cells in murine gastritis was apparently not affected by the presence of anti-CTLA4 antibody.⁵ Some mechanisms by which CTLA4 influences the suppressive effect of Treg have been postulated: it is possible that anti-CTLA4 antibody blocks CTLA4 on the Treg cells; the antibody could activate CD4+CD25- T cells; and the anti-CTLA4 antibody could render the CD4+CD25- T cells refractory to the suppressive effect of the Treg cells by masking their CTLA4 Ag.⁴

Blocking CTLA4 or depleting Treg cells could break self tolerance causing nonspecific autoimmune pathologies.⁶ Recently, a possible synergy of immune reactivity to defined tumor and self antigens after reduction of Treg has been hypothesized.⁷ In a Treg-deprived environment, tumor cells primed the immune system, with consequent tumor regression, though Treg-depletion enhanced autoimmunity to mouse thyroglobulin. Anti-CTLA-4 antibody given to patients with metastatic melanoma induces durable objective clinical responses associated with the induction of autoimmune adverse effects.⁸ However, the autoimmune and antitumor effects seen after CTLA-4 blockade are not due to inhibition or depletion of Treg, but appear to act through direct activation of CD4+ and CD8+ effector cells.²

Finally, the mechanism by which CTLA4 influences the suppressive effect of Treg still remains unclear. We strongly agree with Beck et al¹ that "examination of Treg cells in tumor or other relevant tissues may be needed to fully investigate this issue." ¹

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflict of interest.

REFERENCES

1. Beck KE, Blansfield JA, Tran KQ, et al: Enterocolitis in patients with cancer after antibody blockade of cytotoxic t-lymphocyte-associated antigen 4. J Clin Oncol 24:2283-2289, 2006[Abstract/Free Full Text]

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

3. Salomon B, Lenschow DJ, Rhee L, et al: B7/CD28 costimulation is essential for the homeostasis of the CD4⁺CD25⁺ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431, 2000[CrossRef][Medline]

4. Liu H, Hu B, Xu D, et al: CD4+CD25+ regulatory T cells cure murine colitis: The role of IL-10, TGF-beta, and CTLA4. J Immunol 171:5012-5017, 2003[Abstract/Free Full Text]

5. Takahashi T, Tagami T, Yamazaki S, et al: Immunologic self-tolerance maintained by CD25⁺CD4⁺ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303, 2000[Abstract/Free Full Text]

6. Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100:8372-8377, 2003[Abstract/Free Full Text]

7. Wei WZ, Jacob JB, Zielinski JF, et al: Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4+ CD25+ regulatory T cell-depleted mice. Cancer Res 65:8471-8478, 2005[Abstract/Free Full Text]

8. Attia P, Phan GQ, Maker AV, et al: Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-CTLA-4. J Clin Oncol 23:6043-6053, 2005[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ferretti, G. Articles by Cognetti, F. Search for Related Content PubMed PubMed Citation Articles by Ferretti, G. Articles by Cognetti, F. Social Bookmarking                            What's this?