Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells.
IL-2 immunotherapy is an attractive treatment option for certain metastatic cancers. However, administration of IL-2 to patients can lead, by ill-defined mechanisms, to toxic adverse effects including severe pulmonary edema. Here, we show that IL-2-induced pulmonary edema is caused by direct interaction of IL-2 with functional IL-2 receptors (IL-2R) on lung endothelial cells in vivo. Treatment of mice with high-dose IL-2 led to efficient expansion of effector immune cells expressing high levels of IL-2Rbetagamma, including CD8(+) T cells and natural killer cells, which resulted in a considerable antitumor response against s.c. and pulmonary B16 melanoma nodules. However, high-dose IL-2 treatment also affected immune cell lineage marker-negative CD31(+) pulmonary endothelial cells via binding to functional alphabetagamma IL-2Rs, expressed at low to intermediate levels on these cells, thus causing pulmonary edema. Notably, IL-2-mediated pulmonary edema was abrogated by a blocking antibody to IL-2Ralpha (CD25), genetic disruption of CD25, or the use of IL-2Rbetagamma-directed IL-2/anti-IL-2 antibody complexes, thereby interfering with IL-2 binding to IL-2Ralphabetagamma(+) pulmonary endothelial cells. Moreover, IL-2/anti-IL-2 antibody complexes led to vigorous activation of IL-2Rbetagamma(+) effector immune cells, which generated a dramatic antitumor response. Thus, IL-2/anti-IL-2 antibody complexes might improve current strategies of IL-2-based tumor immunotherapy.
Krieg
Carsten
C
Division of Immunology and Allergy, University Hospital of Lausanne, CH-1011 Lausanne, Switzerland.
Létourneau
Sven
S
Pantaleo
Giuseppe
G
Boyman
Onur
O
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000008:administration & dosage / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008214:Lymphocytes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011654:Pulmonary Edema / Q000209:etiology / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D018398:Homeodomain Proteins; C508594:IL2 protein, human; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; C064658:RAG-1 protein