Role of CD3ζ expression and arginase activity in predicting response and survival in metastatic renal cell carcinoma (mRCC) patients receiving IL-2

Abstract

2535 Background: A decrease in the T cell receptor ζ chain expression has been described in malignancy and chronic infections. The association with response to treatment and the mechanisms leading to this diminished expression are unclear. In vitro models suggest that arginase production may decrease CD3ζ expression.Methods: We examined the expression of CD3ζ chain and arginase activity in preRx samples of peripheral blood mononuclear cells from pts with mRCC receiving IL-2 Rx on a CWG Phase III trial, ζ chain expression was studied by florescence intensity (MFI) and serum arginase activity by conversion of arginine to ornithine. Results were compared to blood obtained from 33 healthy normal volunteers (NV). Results: Of 106 with a pre-Rx blood samples 18 pts responded (7 CR, 11 PR). MFI for CD3 ζ was 21.39 +/- 8.15 for the pts vs 35.43 +/- 12.24 for the NV. Mean arginase was 128.55 for pts vs 32.63 for NV. Serum arginase levels and CD3 ζ chain expression were inversely related (r= -0.31, p<0.01 ). Low and extremely low ζ expression was defined as 1 or 2 SD below the mean of the NV's. Median survival was 26, 19 and 14mos and tumor response was 19% (8/42), 18% 10/56 and 0% (0/8) for pts with normal, low and extremely low ζ expression. Arginase was 128.55 for pts vs 32.63 for NV. No correlation of survival or response with arginase expression was observed. . Data on other immune abnormalities including CD14+, CD4/CD25 reg T cells, LCK and Jak-3, and inducible cytokines are still being analyzed. Conclusions: These data suggest that mRCC is associated with decrement in ζ chain and increased arginase expression. Decreased ζ chain is associated with poor response and survival outcome Given the absence of response in pts with low ζ chain in these data, its role as a potential selection factor should be further investigated. The role of arginase in the loss of CD3ζ and in response to immunotherapy requires further study No significant financial relationships to disclose.