IL-4 RECEPTORS ON MURINE SOLID TUMORS AND TUMOR INFILTRATING LYMPHOCYTES

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We have examined the presence of the Interleukin-4 receptor (IL-4R) on methylcholanthrene (MCA-106, MCA-102 and MC-38) and viral DNA (G-2TS and 14-2TS) induced murine sarcoma cells. We demonstrated for the first time that murine solid tumor cells express a single class of high affinity IL- 4R. About 800 IL-4 binding sites/cell with a dissociation constant (KD) of 115 pM was observed. These receptors are similar in characteristics to that observed by us on TIL cells and by others on T and B lymphocytes, mast cells and macrophages. By Northern blot analysis of tumor cells, a single mRNA species of 3.9 Kb was observed. By immunoperoxidase staining, 81-92% from fresh MCA-106 tumors were positive for IL-4 receptors, while only 7-10% of tumor infiltrating cells were Thy 1.2 and less than 1% Mac- 1. The receptors on the tumor surface are internalized after binding to a chimeric protein between IL-4 and pseudomonas exotoxin (IL-4-PE40). Using IL-4-PE40, we observed that IL-4-PE40 was cytotoxic (determined by inhibition of protein synthesis by tritiated-Leucine uptake) to MCA-106 tumor cells in a dose-dependent manner. PE40, a nonchimeric protein which cannot bind to the IL-4R, did not inhibit protein synthesis in tumor cells. IL-4-PE40M, a chimeric mutant protein which can bind to IL-4 receptors but does not have the capability to inhibit protein synthesis, was not cytotoxic to tumor cells. These studies strongly suggest that IL- 4R on murine MCA-106 sarcoma cells is internalized when occupied by IL-4- PE40 and may be functional. Furthermore, a neutralizing antibody (11B11) to IL-4, completely abolished the protein synthesis inhibitory activity of IL-4-PE40. Taken together, these data suggest that the IL-4 receptor may be a target for IL-4-Toxin therapy. We are currently investigating possible regulation of IL-4R on tumor cells and on TIL cells. This project is currently active.