| T cell-mediated tumor rejection relies on the balance between anti-tumor T cell function and the suppressive mechanisms at work in the tumor microenvironment. Surmounting this unfavorable environment by augmenting T cell proliferation, persistence, and effector functions are primary goals of improving tumor-specific adoptive immunotherapy for cancer. The gammac-cytokine family members IL-2, IL-7, IL-15, and IL-21 are T cell growth factors and positive modulators of T cell function. We hypothesized that retroviral-mediated constitutive overexpression of these cytokines in tumor-specific human primary T cells would allow local delivery of the anti-tumor cytokine directly to the tumor bed, leading to enhanced tumor rejection. We directly compared the anti-tumor functions of each cytokine in vitro and in a novel in vivo immunodeficient mouse model. In comparison to control-transduced T cells, overexpression of IL-2 or IL-15 increased the ability of T cells to accumulate in response to antigenic stimulation, express the anti-apoptotic molecule Bc1-2, upregulate the effector molecules granzyme A, IFN-gamma, and TNF-alpha, and potently eradicate established, systemic lymphomas from NOD/SCID/gammac null mice. Likewise, T cells overexpressing IL-7 cleared tumors, but most likely did so via a mechanism involving an enhanced ability to survive and proliferate, rather than through an upregulation of effector function. The greatest in vivo efficacy was observed with adoptive transfer of IL-21-transduced T cells, however in vitro functional assays did not uncover an underlying mechanism. These data clarify the overlapping anti-tumor effects of IL-2, IL-7, IL-15, and IL-21 on human T cells and suggest a means to amplify adoptive T cell therapy. |
