Sequential immune monitoring in patients with melanoma and renal cell carcinoma treated with high-dose interleukin-2: immune patterns and correlation with outcome
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Interleukin-2 (IL-2) therapy leads to clinically relevant responses in 10–16 % of patients with metastatic melanoma (MMEL) or 10–30 % of patients with metastatic renal cell carcinoma (MRCC). To date, no biomarkers have been validated to identify patients who are likely to respond. We hypothesized that changes in T cell subset distribution in patients undergoing IL-2 therapy may correlate with treatment outcomes. Immune profiles of 64 patients (27-MMEL, 37-MRCC) were evaluated using flow cytometry at baseline, during (≥three doses) and at the end of treatment cycle (30 ± 6 h after last dose), through two courses of IL-2 therapy. Changes in distribution and phenotype of circulating CD4 and CD8 lymphocyte subsets were compared (1) based on cancer types and (2) intra-patient during the course of the IL-2 therapy. Exploratory analysis of immunologic profiles was also performed based on treatment outcome. Independent of cancer type, IL-2 led to a transient decrease of circulating effector lymphocytes, while regulatory T cells gradually increased. Interleukin-2 differentially affected a subset of CD8 T cell expressing Foxp3, depending on malignancy type. In MMEL patients, IL-2 gradually expanded circulating CD8 Foxp3+ cells; in MRCC patients, IL-2 transiently increased expression of CD103 and CCR4 homing markers. Monitoring of adaptive immune variables early on and during the course of IL-2 therapy revealed transient alterations in immune profiles, specific to MMEL and MRCC patients, related to immune balance (and ultimately response to IL-2 therapy) or T cell egress from the circulation.
KeywordsMelanoma Renal cell carcinoma Interleukin-2 Immune monitoring Biomarkers
Forkhead box P3
Generalized estimating equations
Minimal information about T cell assay
Metastatic renal cell carcinoma
Peripheral mononuclear cells
Response evaluation criteria in solid tumor
Regulatory T cell
Upper limit of normal
This study was funded in part by a seed grant from the Carolinas Healthcare Foundation, the Purple Promise Foundation to end Melanoma and the Freedland Foundation. We thank Dr. Carol Farhangfar for comments on the manuscript, Dr. H James Norton for helping with statistical analysis, Joey Armstrong and Kendall Carpenter for compiling clinical data and Patricia Hevey for semantic and syntactic corrections.
Conflict of interest
Drs. Amin and White are members of Prometheus speaker’s bureau. All other authors have no commercial or consultancy conflict of interest.
- 1.Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17(7):2105–2116PubMedGoogle Scholar
- 3.Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT et al (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316(15):889–897. doi: 10.1056/NEJM198704093161501 PubMedCrossRefGoogle Scholar
- 9.Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M, Atkins MB, Dutcher JP, Micetich KC, Weiss GR et al (1993) Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11(10):1969–1977PubMedGoogle Scholar
- 14.White RL Jr, Amin A (2011) Cancer immunotherapy. Surg Oncol Clin N Am 20(3):531–554, ix. doi: 10.1016/j.soc.2011.01.010
- 15.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRefGoogle Scholar
- 17.Kmieciak M, Gowda M, Graham L, Godder K, Bear HD, Marincola FM, Manjili MH (2009) Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med 7:89. doi: 10.1186/1479-5876-7-89 PubMedCentralPubMedCrossRefGoogle Scholar