title: Low-dose interleukin-2 impairs host anti-tumor immunity and inhibits therapeutic responses in a mouse model of melanoma.
abstract: Recombinant interleukin-2 (rIL-2) is associated with objective responses in 15-20 % of patients with metastatic melanoma and renal cell carcinoma. More recently, rIL-2 has also demonstrated improved clinical activity in patients with melanoma. Given the toxicity of high-dose rIL-2 and the availability of many new immunotherapy agents, it has been suggested that lower doses of rIL-2 may be preferred for combination clinical studies. In order to determine the impact of low doses of rIL-2 on anti-tumor immunity and therapeutic effectiveness, we challenged C57BL/6 mice with poorly immunogenic B16-F10 melanoma and treated them with varying doses of rIL-2 (range 103-105IU). Tumor growth at day 14 was significantly reduced when rIL-2 was administered at 10,000 (P < 0.02) and 100,000 (P < 0.02) IU doses, but tumor growth was significantly increased when mice were treated at 1000 IU rIL-2 (P < 0.02), as compared to placebo treatment. While the proportions of CD8+ and CD4+ T cells in the tumor were similar at all doses tested, the proportion of NK cells was decreased and the proportion of Tregs was increased in tumors exposed to low-dose rIL-2. The ratio of gp100-specific CD8+ to CD4+ regulatory T cells was increased in tumors treated at 10,000 and 100,000 IU of rIL-2 but was decreased at the 1000 IU dose compared to placebo-treated mice. These findings suggest that low-dose rIL-2 may impair host anti-tumor immunity and promote tumor growth. Early-phase adjuvant and combination clinical studies should include patient cohorts with higher doses of rIL-2.
authors.affiliation: Division of Surgical Oncology Research, Section of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA.|Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.|Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL, USA.|Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zloza
authors.affiliation: Division of Surgical Oncology Research, Section of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Dharmadhikari
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Huelsmann
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Broucek
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, IL, USA.
authors.forename: Tasha
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Division of Surgical Oncology Research, Section of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Kohlhapp
authors.affiliation: Division of Surgical Oncology Research, Section of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA. howard.kaufman@rutgers.edu.|Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. howard.kaufman@rutgers.edu.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D007376:Interleukin-2
keywords: CD8+ T cell; Cancer vaccines; Immunotherapy; Interleukin-2; Natural killer cell; Regulatory T cell