1Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; 2Department I of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by tumor recurrence and incomplete responses. Accumulating evidence suggests that the microenvironment of established tumors reduces numbers and responsiveness of intra-tumor effector T cells. Here, we aim to direct the tumor microenvironment in favor of a successful immune response by locally inducing production of interleukin (IL-)12 and IL-18 by administered T cells. To this end, we have engineered T cells with a T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 and IL-18, and consequently enhanced levels of IFNγ, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells transduced with a TCR and inducible (i)IL-12 (TCR+iIL-12 T cells) to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of inflammatory cytokines in blood and enhanced infiltration of macrophages into the tumor. Notably, TCR+iIL-12 T cells demonstrated enhanced expression of co-inhibitory receptors and markers of regulatory T cells, and its numbers were reduced in blood. In contrast, transfer of TCR+iIL-18 T cells was safe and significantly reduced tumor burden, prolonged overall survival, and these T cells showed a favorable profile of T cell co-stimulatory and inhibitory receptors. In conclusion, we observed that treatment with TCR+iIL12 T cells is harmful, whereas treatment with TCR+iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response.
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