Original Communications| Volume 129, ISSUE 6, P749-756, June 2001

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Loss of T-cell receptor-CD3ζ and T-cell function in tumor-infiltrating lymphocytes but not in tumor-associated lymphocytes in ovarian carcinoma


      Background. Impaired T-cell function has been noted in tumor-infiltrating lymphocytes (TIL). Recently, loss of function was found to be associated with modifications in T-cell receptor complex (TCR)-mediated signaling. A common feature is loss or reduced expression levels of the signaling chain, TCRζ. We evaluated whether loss of function in TIL and tumor-associated lymphocytes (TAL) from patients with ovarian cancer is associated with changes in TCRζ expression, and 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 TCRζ and CD3ϵ was evaluated in fresh TIL and TAL by the Western blot technique. Finally, various conditions within a tumor environment were tested for their effect on TCRζ and CD3ϵ. Results. TIL, but not TAL, were significantly impaired in their proliferative response, even when both populations were derived from the same patient (P <.05). Reduced proliferation levels were associated with loss of expression of TCRζ but not of CD3ϵ. Exposure of normal T cells to relative ischemia or heat shock, or culture in medium without IL-2, did not significantly reduce expression of TCRζ compared with CD3ϵ. However, coculture of T cells with tumor-derived macrophages or tumor-derived factors led to a selective loss of TCRζ compared with CD3ϵ (P <.05). Further analysis suggested that oxides such as hydrogen peroxide secreted by macrophages may be responsible for loss of TCRζ and high molecular weight factors secreted by certain tumors. Conclusions. TIL but not TAL show impaired T-cell function, which is associated with loss of TCRζ. In addition to macrophages secreting oxides, loss of TCRζ may be caused by tumor-derived soluble factors. (Surgery 2001;129:749-56.)
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        • Weissman AM
        • Samelson LE
        • Klausner RD
        A new subunit of the human T-cell antigen receptor complex.
        Nature. 1986; 324: 480-482
        • Fraser JD
        • Straus D
        • Weiss A.
        Signal transduction events leading to T-cell lymphokine gene expression.
        Immunol Today. 1993; 14: 357-360
        • Levey DL
        • Srivastava PK
        Alterations in T cells of cancer-bearers: whence specificity?.
        Immunol Today. 1996; 17: 365-368
        • Mizoguchi H
        • O'Shea JJ
        • Longo DN
        • Loeffler CM
        • McVicar DW
        • Ochoa AC
        Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice.
        Science. 1992; 258: 1795-1798
        • Zier K
        • Gansbacher B
        • Salvadori S.
        Preventing abnormalities in signal transduction of T cells in cancer: the promise of cytokine gene therapy.
        Immunol Today. 1996; 17: 39-45
        • Nakagomi H
        • Petersson M
        • Magnusson I
        • Juhlin C
        • Matsuda M
        • Mellstedt H
        • et al.
        Decreased expression of the signal-transducing ζ chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma.
        Cancer Res. 1993; 53: 5610-5612
        • Kono K
        • Salazar-Onfray F
        • Petersson M
        • Hansson J
        • Masucci G
        • Wasserman K
        • et al.
        Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity.
        Eur J Immunol. 1996; 26: 1308-1313
        • Aoe T
        • Okamoto Y
        • Saito T.
        Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex.
        J Exp Med. 1995; 181: 1881-1886
        • Kolenko V
        • Wang Q
        • Riedy MC
        • O'Shea J
        • Ritz J
        • Cathcart MK
        • et al.
        Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling.
        J Immunol. 1997; 159: 3057-3067
        • Von Bernstorf W
        • Spanjaard RA
        • Chan AK
        • Lockhart D
        • Sadanaga N
        • Wood I
        • et al.
        Pancreatic cancer cells can evade immune surveillance via nonfunctional Fas (APO-1/CD95) receptors and aberrant expression of functional Fas ligand.
        Surgery. 1999; 125: 73-84
        • O'Connell J
        • Bennett MW
        • O'Sullivan GC
        • Collins JK
        • Shanahan F.
        The Fas counterattack: cancer as a site of immune privilege.
        Immunol Today. 1999; 20: 46-52
        • Gastman BR
        • Johnson DE
        • Whiteside TL
        • Rabinowich H.
        Caspase-mediated degradation of T-cell receptor ζ-chain.
        Cancer Res. 1999; 59: 1422-1427
        • Peoples GE
        • Schoof DD
        • Raven Andrews JV
        • Goedegebuure PS
        • Eberlein TJ
        T cell recognition of ovarian cancer.
        Surgery. 1995; 114: 227-234
        • Yoshino I
        • Goedegebuure PS
        • Peoples GE
        • Lee K-Y
        • Eberlein TJ
        Human tumor-infiltrating CD4+ T cells react to B cell lines expressing heat shock protein 70.
        J Immunol. 1994; 153: 4149-4158
        • Cardi G
        • Heaney JA
        • Schned AR
        • Phillips DM
        • Branda MT
        • Ernstoff MS
        T-cell receptor ζ-chain expression on tumor-infiltrating lymphocytes from renal cell carcinoma.
        Cancer Res. 1997; 57: 3517-3519
        • Anderson P
        • Blue M-L
        • O'Brien C
        • Schlossman SF
        Monoclonal antibodies reactive with the T cell receptor ζ chain: production and characterization using a new method.
        J Immunol. 1989; 143: 1899-1904
        • Bodmer S
        • Strommer K
        • Frei K
        • Siepl C
        • DeTribolet N
        • Heid I
        • et al.
        Immunosuppression and transforming growth factor-β in glioblastoma: preferential production of transforming growth factor-β.
        J Immunol. 1989; 143: 3222-3229
        • Botti C
        • Seregni E
        • Ferrari L
        • Martinetti A
        • Bombardieri E.
        Immunosuppressive factors: role in cancer development and progression.
        Int J Biol Markers. 1998; 13: 51-69
        • Chan AK
        • Lockhart DC
        • Von Bernstorff W
        • Spanjaard RA
        • Joo H-G
        • Eberlein TJ
        • et al.
        Soluble MUC1 secreted by human epithelial cancer cells mediates immune suppression by blocking T-cell activation.
        Int J Cancer. 1999; 82: 721-726
        • Hoffmann JC
        • Kruger H
        • Luhrs J
        • Hamm H.
        Detection of soluble adhesion molecules in pleural effusions.
        Chest. 1996; 110: 107-113
        • Miescher S
        • Whiteside T
        • Carrel TL
        • von Fliedner V.
        Functional properties of tumor-infiltrating and blood lymphocytes in patients with solid tumors: effects of tumor cells and their supernatants on proliferative responses of lymphocytes.
        J Immunol. 1986; 136: 1899-1907
        • Miescher S
        • Stoeck M
        • Qiao L
        • Barras C
        • Barrelet L
        • von Fliedner V.
        Proliferative and cytolytic potentials of purified human tumor-infiltrating T lymphocytes. Impaired response to mitogen-driven stimulation despite T-cell receptor expression.
        Int J Cancer. 1988; 42: 659-666
        • Zier KS
        • Salvadori S
        • Cronin KC
        • Gansbacher B.
        Vaccination with IL-2—secreting tumor cells stimulates the generation of IL-2 responsive T cells and prevents the development of unresponsiveness.
        Cancer Gene Ther. 1994; 1: 43-50
        • Shrikant P
        • Khoruts A
        • Mescher MF
        CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
        Immunity. 1999; 11: 483-493
        • Rabinowich H
        • Reichert TE
        • Kashii Y
        • Gastman BR
        • Bell MC
        • Whiteside TL
        Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells.
        J Clin Invest. 1998; 101: 2579-2588
        • Schneider P
        • Holler N
        • Bodmer JL
        • Hahne M
        • Frei K
        • Fontana A
        • et al.
        Conversion of membrane-bound Fas (CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity.
        J Exp Med. 1998; 187: 1205-1213
        • Sieg S
        • Smith D
        • Kaplan D.
        Differential activity of soluble versus cellular Fas ligand: regulation by an accessory molecule.
        Cell Immunol. 1999; 195: 89-95
        • McKallip R
        • Li R
        • Ladisch S.
        Tumor gangliosides inhibit the tumor-specific immune response.
        J Immunol. 1999; 163: 3718-3726
        • Kolenko V
        • Rayman P
        • Roy B
        • Cathcart MK
        • O'Shea J
        • Tubbs R
        • et al.
        Downregulation of JAK3 protein levels in T lymphocytes by prostaglandin E2 and other cyclic adenosine monophosphate-elevating agents: impact on interleukin-2 receptor signaling pathway.
        Blood. 1999; 93: 2308-2318
        • Takahashi K
        • Goedegebuure PS
        • Eberlein TJ
        Treatment with anti-Fas ligand antibody eliminates immunosuppression by Lewis lung carcinoma cells through Fas ligand (abstract).
        Proc Am Assoc Cancer Res. 2000; 41: 2
        • Salvadori S
        • Gansbacher B
        • Pizzimenti AM
        • Zier KS
        Abnormal signal transduction by T cells of mice with parental tumors is not seen in mice bearing IL-2—secreting tumors.
        J Immunol. 1994; 153: 5176-5182
        • Ghosh P
        • Sica A
        • Young HA
        • Ye J
        • Franco JL
        • Wiltrout RH
        • et al.
        Alterations in NFkB/Rel family proteins in splenic T-cells from tumor-bearing mice and reversal following therapy.
        Cancer Res. 1994; 54: 2969-2972