Repression of IL-2 mRNA translation in primary human breast cancer tumor infiltrating lymphocytes
Tumor infiltrating lymphocytes (TIL) are abundant in primary human carcinomas but display diminished proliferative response to TCR ligation in vitro. We demonstrate by immunocytochemistry analysis that breast carcinoma TII. express both early and late cell surface activation antigens indicative of ongoing immune response. However, TIL were deficient in IL-2 receptor expression: CD25 was detected in only 1 out of 24 samples and CD122 was detected in only 2 samples. The common gamma subunit (CD132) was expressed in 21/24 tumors. RT-PCR analysis of tumor RNA showed moderate levels of CD122 mRNA in 5 out of 19 samples, 9 samples expressed no mRNA, and 5 samples expressed only very low (but detectable) mRNA. Similarly, moderate levels of CD25 RNA was detected in 1 tumor, very low levels were found in 4 tumors, and 14 tumors expressed no RNA. Furthermore, isolated breast cancer TILs were defective both in proliferative response and IL-2 receptor mRNA expression but recover when incubated in the presence of recombinant IL-2. 19/24 tumor samples expressed B7-1, B7-2, CD28, and CTLA-4 protein showing that absence of co-stimulator proteins or counter ligands was not the basis for TIL proliferative deficit. By bioassay of tumor explants IL-2 was not detected although mRNA encoding IL-2 was produced and was able to be translated in vitro. These findings show that human breast cancer TIL are anergic and suggest that tumor-induced repression of IL-2 RNA translation is the basis of failure to express the IL-2 receptor and subsequent T cell hyporesponsiveness.
Frey, AB; Lopez, C; Feiner, H; Shapiro, R; Marks, J; Rao, TD
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