IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice.
The gamma(c)-cytokines are critical regulators of immunity and possess both overlapping and distinctive functions. However, comparative studies of their pleiotropic effects on human T cell-mediated tumor rejection are lacking. In a xenogeneic adoptive transfer model, we have compared the therapeutic potency of CD19-specific human primary T cells that constitutively express interleukin-2 (IL-2), IL-7, IL-15, or IL-21. We demonstrate that each cytokine enhanced the eradication of systemic CD19(+) B-cell malignancies in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gamma(c)(null) mice with markedly different efficacies and through singularly distinct mechanisms. IL-7- and IL-21-transduced T cells were most efficacious in vivo, although their effector functions were not as enhanced as IL-2- and IL-15-transduced T cells. IL-7 best sustained in vitro T-cell accumulation in response to repeated antigenic stimulation, but did not promote long-term T-cell persistence in vivo. Both IL-15 and IL-21 overexpression supported long-term T-cell persistence in treated mice, however, the memory T cells found 100 days after adoptive transfer were phenotypically dissimilar, resembling central memory and effector memory T cells, respectively. These results support the use of gamma(c)-cytokines in cancer immunotherapy, and establish that there exists more than 1 human T-cell memory phenotype associated with long-term tumor immunity.
Markley
John C
JC
Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Sadelain
Michel
M
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D015851:Interleukin-7 / Q000096:biosynthesis / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology*; D016393:Lymphoma, B-Cell; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014183:Transplantation, Heterologous; D000098546:Interleukin-21
D018941:Antigens, CD19; C508594:IL2 protein, human; C508605:IL7 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; D000098546:Interleukin-21