title: Local hyperthermia abrogates the anti-immunotherapeutic effect of interleukin-8.
abstract: The therapeutic efficacy of cellular immunotherapy depends not only on the anti-tumor activity of the administered effector cells but also on their ability to gain access to the tumor by extravasation. Although interleukin-8 (IL-8) has been shown to prevent the vascular leak associated with IL-2, it also abrogates the anti-tumor effect of IL-2. We undertook these studies to determine if LHT could abrogate the anti-immunotherapeutic effect of IL-8, since IL-8 inhibits leukocyte adhesion. C57BL/6 mice were divided into four groups of six animals each after induction of MCA-105 fibrosarcoma inoculated into the right hindlimb on day 0 and were treated beginning on day 3 as follows: no therapy, IL-2 alone (1.02 x 10(6) IU ip tid on days 3-7), IL-2 + IL-8 (9.6 ng ip tid on days 3-7), and IL-2 + IL-8 + LHT (45C x 15 min on days 3, 5, and 7). Tumor growth was measured on days 10-21 and analyzed by Wilcoxon rank-sum analysis. IL-2 reduced tumor growth significantly (P < .05) compared to no therapy, and IL-8 abrogated the anti-tumor effect of IL-2, resulting in tumor growth in animals receiving IL-2 + IL-8, similar to the no therapy group (P > .05). However, addition of LHT to IL-2 + IL-8 resulted in significantly (P < .05) less tumor growth than no therapy or IL-2 + IL-8. Activity of the mice was scored as an indicator of systemic toxicity. We found that IL-8 was able to increase the activity (P = .07) of the mice when administered with IL-2. These results suggest that IL-8 may protect the tumor-bearing animal from the systemic toxicity of IL-2, while LHT abrogates the anti-immunotherapeutic effect of IL-8.
authors.affiliation: Department of Surgery, University of Maryland, Baltimore.
authors.forename: D M
authors.initials: DM
authors.lastname: Geehan
authors.forename: D F
authors.initials: DF
authors.lastname: Fabian
authors.forename: A T
authors.initials: AT
authors.lastname: Lefor
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D003131:Combined Modality Therapy; D005260:Female; D005354:Fibrosarcoma / Q000628:therapy*; D006979:Hyperthermia, Induced; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D016209:Interleukin-8 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D007376:Interleukin-2; D016209:Interleukin-8