Combination therapy using IL-2 and anti-CD25 results in augmented natural killer cell-mediated antitumor responses.
Interleukin (IL)-2 has been extensively examined to promote clinical T and natural killer (NK) cell responses. Regulatory T cells (Tregs) have been shown to regulate many aspects of the immune system, including NK cell-mediated responses. We have demonstrated that in vivo administration of IL-2 led to activation and expansion of both NK cells and immunosuppressive Tregs. Therefore, we attempted to augment NK cell antitumor effects by concurrently depleting Tregs using anti-CD25. Increased NK cell activation by IL-2 was found to be correlated with an increase in classical, short-term NK cell in vitro killing assays regardless of the depletion of Tregs. But when splenocytes of the treated mice were used in long-term tumor outgrowth experiments, we observed that prior depletion of Tregs from IL-2 administration led to improved antitumor effects compared with either treatment alone. Importantly, these in vitro data are correlated with subsequent in vivo survival of leukemia-bearing mice, in which co-treatment of IL-2 with anti-CD25 led to significantly improved survival compared with mice treated with either IL-2 alone or with Treg depletion. Prior depletion of NK1.1(+) cells, but not of CD8(+) cells, completely abrogated all antitumor effects mediated by IL-2 and anti-CD25 combination therapy. These findings demonstrate that superior NK cell-mediated antileukemic effects can be achieved with IL-2 administration and concurrent depletion of CD25(+) cells.
Hallett
William H D
WHD
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada Reno, Reno, Nevada.
Ames
Erik
E
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada Reno, Reno, Nevada.
Álvarez
Maite
M
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada Reno, Reno, Nevada.
Barao
Isabel
I
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada Reno, Reno, Nevada.
Taylor
Patricia A
PA
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, Minnesota.
Blazar
Bruce R
BR
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, Minnesota.
Murphy
William J
WJ
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada Reno, Reno, Nevada. Electronic address: wmurphy@medicine.nevada.edu.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000188:drug therapy / Q000401:mortality / Q000628:therapy*; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit