Memory T cells in human tumor and chronic inflammatory microenvironments: Sleeping beauties re-awakened by a cytokine kiss

Human tumors often progress and spread in spite of the presence of large numbers of CD4+ and CD8+ T cells with activated or memory cell phenotypes. The T cells in the microenvironment of human lung tumors fail to be activated in response to stimulation via the T cell receptor and CD28 under conditions that fully activate T cells derived from the peripheral blood of the cancer patients. A combination of regulatory mechanisms which are also observed in a variety of different chronic inflammatory conditions may contribute to the T cell unresponsiveness, and to their inability to respond to and kill tumor cells. The non-responsiveness of memory T cells isolated from human lung tumors and non-malignant chronic inflammatory tissues can be reversed in vitro by a brief pulse with IL-12, and the local and sustained release of exogenous IL-12 into the microenvironment of human tumor xenografts in SCID mice re-activates the tumor-associated T cells in situ. In the later case, the T cells proliferate, secrete interferon-gamma and initiate a cascade of events that culminate in the eradication of tumor cells from the xenograft. In transplantable and spontaneously developing tumors of mice the injection of a single tumor nodule with IL-12 loaded biodegradable microspheres activates tumor-associated T cells to kill tumor cells in situ, and provokes a systemic antitumor response that results in the eradication of distant metastatic tumor nodules that are not treated with the cytokine. These mice exhibit a systemic tumor specific immunity as they resist a second challenge with the same (but not a different) tumor. These findings suggest that it will be possible to provoke a systemic anti-tumor immunity in cancer patients by the direct injection of IL-12 loaded biodegradable microspheres or liposomes to locally deliver very low but sustained doses of IL-12 into a single tumor site. This strategy which is based upon the ability of IL-12 to re-activate tumor-associated T cells is termed in situ tumor vaccination.