Defective T cell immune response is thought to contribute to the failure to effectively eliminate antigenic tumor which, if possible to revert, may provide an opportunity for immunotherapy of cancer. The widespread association with cancers of various types (including; breast, ovarian, cervical, prostate, squamous cell and renal cell carcinomas, and; melanoma, glioma, and lymphoma) and the correlation between T cell signaling defects and disease stage is strongly suggestive of a causal association. We have studied the function of T cells which infiltrate primary human breast carcinoma. Tumor infiltrating lymphocytes (TL) from human breast carcinoma express several cell surface activation antigens but not the Interleukin-2 Receptor alpha and beta chains. IL-2R subunit mRNA is not expressed showing the defect is regulated at the transcriptional level. Furthermore, isolated TIL are severely defective in both proliferation and secretion of IL-2 in response to TCR ligation in vitro. When purified and exposed briefly to rIL-2, TIL recover both the proliferative and IL-2 secretion defects coincident with upregulation of IL-2R subunits suggesting TIL are rendered anergic in situ. Expression of early activation markers but not the high affinity IL-2R by T cells in the tumor microenvironment, together with the IL-2 secretion and proliferation deficits, suggests that tumor-reactive T cells are primed by exposure to antigen but have a block in the IL-2 signaling pathway which is postulated to be the basis of the hyporesponsive state of TIL. Paradoxically TIL accumulate mRNA encoding IL-2 although IL-2 mRNA is not translated. Our data is consistent with the hypothesis that the failure to translate IL-2 mRNA is the basis for the lack of IL-2 secretion which in turn prevents IL-2R upregulation and causes the subsequent proliferative defect in TIL. We have developed an assay which shall be used to characterize the involvement of factors which bind to IL-2 mRNA in anergic tumor infiltrating lymphocytes. The proposed research shall test the hypothesis that the tumor microenvironment induces the activity of an mRNA binding factor in TIL that stabilizes IL-2 mRNA and sequesters it unable to be translated.
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| Radoja, S; Frey, A B (2000) Cancer-induced defective cytotoxic T lymphocyte effector function: another mechanism how antigenic tumors escape immune-mediated killing. Mol Med 6:465-79 |
