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Journal of Clinical Oncology, Vol 24, No 20 (July 10), 2006: pp. e35-e36 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5557
In ReplyThe Tumor Immunology Laboratory, Columbia University, New York, NY We recently reported that the numbers of CD4+CD25hi regulatory T cells (TREG) were elevated in patients with metastatic melanoma and renal carcinoma.1 The increased frequency of TREGs remained elevated in patients who failed treatment with high-dose interleukin 2 (IL-2), consistent with other reports.2 However, the TREG frequency returned to normal donor levels in those patients who achieved an objective clinical response to IL-2 therapy. Drs Dejaco et al now suggest that IL-2 might be better considered—not as therapeutic anticancer agent —but rather as a means of inducing tolerance in patients with autoimmune disease. This suggestion is supported by data from studies in IL-2 and IL-2 receptor knockout mice that confirmed IL-2-induced lymphopenia augmented TREG activity and led to quiescence of effector T cells.3 Thus as noted by Dejaco et al, IL-2 may be more appropriately thought of as a mediator of peripheral tolerance rather than as a purely immune stimulatory cytokine. This emerging view requires caution as the net effect of IL-2 administration is likely influenced by a number of factors, including the source and dose of antigen, the influence of other cytokines in the local environment, and the nature and intensity of pre-existing cellular responses. An important caveat in our study is that IL-2 did not induce the increase in TREGs but rather these cells are present at higher levels in patients presenting with metastatic cancer. IL-2 therapy actually led to a significant decrease in TREGs in those patients who achieved an objective clinical response but remained elevated in nonresponding patients. The level of TREGs in patients with autoimmune diseases has not been fully established. A significant decrease in the proportion of circulating TREGs within the CD4+ T cell pool was reported in patients with active systemic lupus erythematosus (SLE), possibly related to an increased sensitivity to Fas-induced apoptosis.4 A strong association between the level of TREG depletion and the clinical severity of SLE flare was also found. In contrast, the TREG frequency has been reported to be normal in patients with other systemic autoimmune diseases including rheumatoid arthritis, Sjogren's syndrome, and inflammatory myopathy.5 Thus, before IL-2 could be recommended as a method for increasing the TREG population it will be important to document the baseline level of these cells, confirm their suppressive phenotype, and carefully monitor patients. Our data would suggest that a small subset may actually exhibit a decrease in TREGs after exposure to high-dose IL-2 administration and this might exacerbate clinical symptoms in some patients. Despite renewed interest in the function of IL-2, there are several other issues that remain unresolved with respect to understanding the effects of IL-2 on TREGs and maintenance of tolerance. At present there is a paucity of data on whether TREGs are induced or maintained in an antigen-specific manner. There is evidence that antigen can induce TREGs, which may then operate in an antigen-independent manner.6 Thus, the optimal situation would be to selectively manipulate antigen-specific TREGs and additional research is needed to define methods for identifying such cells in patients with disease. The influence of IL-2 dose is also important, and it is worth noting that much of the in vitro studies of IL-2 effects on TREGs have been done with low doses of IL-2; thus it is possible that lower doses of IL-2 may be more effective at promoting TREG activity in patients with autoimmune disease. This is consistent with studies in melanoma and renal cell carcinoma documenting a lack of clinical benefit for low doses of systemic IL-2 administration.7 Finally, while attention has thus far focused largely on the CD4+CD25+ FoxP3+ TREG population, there are likely other subsets of regulatory cells, such as the recently defined CD8+ regulatory T cell that suppresses autoreactive effector T cells of intermediate avidity.8 It will be important to consider the presence of these other cell populations when contemplating the overall effects of IL-2 on regulating immune responses in vivo. Although the biology of IL-2 remains an interesting and important area of investigation, other methods to manipulate the numbers and/or functional activity of TREGs in vivo merit investigations as well. CD4+CD25+ TREGs could be expanded up to 200-fold ex vivo after isolation from peripheral blood samples and in vitro expansion using anti-CD3 and anti-CD28 stimulation along with high concentrations of recombinant IL-2.9 These TREGs suppressed proliferation and cytokine secretion of responder T cells, and the generation of such populations may allow a more precise method for treating autoimmune diseases rather than exposing patients to the known toxicities of high-dose IL-2 and the indiscriminate potential clinical benefits. The inclusion of immune-based correlates in future clinical trials for patients with cancer, autoimmune diseases, and other immune-based disorders should help clarify the role of IL-2 and other immune response modifiers in regulating the human immune system during disease. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
ACKNOWLEDGMENTS This work was supported by a grant from the Chiron Corporation and National Institutes of Health Grant No. K08. REFERENCES
1. Cesana G, DeRaffele G, Cohen S, et al: Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 (IL-2) for metastatic melanoma and renal cell carcinoma. J Clin Oncol 24:1169-1177, 2006 2. Ahmadzadeh M, Rosenberg SA: IL-2 administration increases CD4+CD25(hi) Foxp3+regulatory T cells in cancer patients. Blood 107:2409-2414, 2006 3. Malek TR, Bayer AL: Tolerance, not immunity, crucially depends on IL-2. Nature Rev Immunol 4:665-674, 2004[CrossRef][Medline] 4. Miyara M, Amoura Z, Parizot C, et al: Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175:8392-8400, 2005 5. Cao D, Malmstrom V, Baecher-Allan C, et al: Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215-223, 2003[CrossRef][Medline] 6. Pccirillo CA, Shevach EM: Naturally-occurring CD4+CD25+ immunoregulatory T cells: Central players in the arena of peripheral tolerance. Semin Immunol 16:81-88, 2004[CrossRef][Medline] 7. Yang JC, Sherry RM, Steinberg SM, et al: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127-3132, 2003 8. Jiang H, Chess L: Regulation of immune responses by T cells. N Engl J Med 354:1166-1176, 2006 9. Earle KE, Tang Q, Zhou X, et al: In vitro expanded human CD4+CD25+ regulatory T cells suppress effectors T cell proliferation. Clin Immunol 115:3-9, 2005[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
