TUMOR-DERIVED MITOGENIC ACTIVITY FOR TUMOR-INFILTRATING LYMPHOCYTES

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The idea that the tumor environment is intrinsically immunogenic and therefore contains lymphocytes with the potential to induce tumor regressio has led to the use of tumor infiltrating lymphocytes (TILS) in clinical trials. In this procedure lymphocytes are grown ex vivo directly from tumor in the presence of the lymphokine interleukin 2 (IL-2); patients are reinfused with their TILs after the latter have been expanded in culture fo several weeks. Although TILs have shown in vivo efficacy, the characteristics of the tumor environment which result in the existence of TILs in vivo remain unclear. Two classes of stimuli -- one derived from cell-cell contact between tumor cells and immunocytes and the other from soluble factors secreted by tumor cells with receptors for them embedded in immunocyte plasma membranes -- are believed to influence T-cell homing and proliferation. Although IL-2 is a potent mitogen for T-cells (the phenotype of TILs), its biosynthesis is mainly confined to immunocytes. In this study the subject of soluble factors other than IL-2 secreted by tumor cell lines as sources of stimuli for TIL proliferation is being addressed. As a starting point for this work, the issue of whether a tumor cell line established from a melanoma tumor could stimulate the growth of TILs derive from melanoma masses was examined. After confirming the amplification potential of three melanoma cell lines, a nonmelanoma line was tested for the same bioactivity and found to be at least as potent a mitogenic source. Mitogenic activity for TILs was found in supernatants from both melanoma an nonmelanoma supernatants; hence, tumor-derived mitogenic activity for TILs could be ascribed to secreted factors. Biochemical and biophysical studies are underway to identify and characterize tumor-derived mitogenic factors for TILS.