Loss of T-cell receptor-CD3 zeta and T-cell function in tumor-infiltratinglymphocytes but not in tumor-associated lymphocytes in ovarian carcinoma

Background. Impaired T-cell function has been noted in tumor-infiltrating l ymphocytes (TIL). Recently, loss of function was found to be associated wit h modifications in T-cell receptor complex (TCR)-mediated signaling. A comm on feature is loss or reduced expression levels of the signaling chain, TCR zeta. We evaluated whether loss of function in TIL and tumor-associated ly mphocytes (TAL) from patients with ovarian cancer is associated with change s in TCR zeta expression, adn which factors can cause these defects. Methods. TIL and TAL were isolated from multiple patients and evaluated for their proliferative capacity by stimulation with a polyclonal stimulus. In addition, expression of TCR zeta and CD3 epsilon was evaluated in fresh TI L and TAL by the Western blot technique. Finally, various conditions within a tumor environment were tested for their effect on TCR zeta and CD3 epsil on. Results. TIL, but not TAL, were significantly impaired in their proliferati ve response, even when both populations were derived from the same patient (P < .05). Reduced proliferation levels were associated with loss of expres sion of TCR<zeta> but not of CD3 epsilon. Exposure of normal T cells to rel ative ischemia or heat shock, or culture in medium without IL-2, did not si gnificantly reduce expression of TCR zeta compared with CD3 epsilon. Howeve r, coculture of T cells with tumor-derived macrophages or tumor-derived fac tors led to a selective loss of TCR zeta compared with CD3 epsilon (P < .05 ). Further analysis suggested that oxides such as hydrogen peroxide secrete d by macrophages may be responsible for loss of TCR<zeta> and high molecula r weight factors secreted by certain tumors. Conclusions. TIL but not TAL show impaired T-cell function, which is associ ated with loss of TCR zeta. In addition to macrophages secreting oxides, lo ss of TCR zeta may be caused by tumor-derived soluble factors.