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Cancer Immunology, Immunotherapy

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01.10.2004 | Review

Down-regulation of ζ-chain expression in T cells: a biomarker of prognosis in cancer?

verfasst von: Theresa L. Whiteside

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 10/2004

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Abstract

The ζ chain is a 16-kDa molecule associated with the T-cell receptor (TCR)-CD3 complex in T lymphocytes and FcγRIII in CD3⁻CD56⁺CD16⁺ natural killer (NK cells). The ζ chain functions as a transmembrane signaling molecule in lymphocytes. Expression of ζ was found to be decreased in CD4⁺ and CD8⁺ T lymphocytes isolated from the tumor site or from the peripheral circulation of patients with cancer. A quantitative flow cytometry–based assay for ζ-chain expression allows for reproducible serial evaluations of disease- or therapy-associated changes in expression of this signaling molecule in phenotypically defined subsets of immune cells. Semiquantitative evaluation of ζ expression in paraffin-embedded tissue specimens can link it to the conventional markers of prognosis or survival. Several distinct mechanisms may be responsible for decreased/absent ζ in T cells of patients with cancer. Monitoring for ζ expression is useful for assessing immune competence in these patients and for following changes in immune competence during anticancer therapies. Correlations made between clinical findings, pathologic results, and ζ expression in immune cells suggest that low/absent ζ is predictive of poor prognosis and survival in patients with cancer. Thus, ζ is emerging as a clinically relevant signaling molecule, which also seems to predict a favorable response to biologic therapies and could be helpful in a selection of patients for immunotherapy trials. Validation studies have yet to be performed for this putative immunologic biomarker. Its consistent use for monitoring under standardized conditions of cancer patients treated with biotherapies may help in confirming a role for ζ as a correlate of prognosis or survival.

Lee KH, Wang E, Nielsen MB, Wunderlich J, Migueles S, Connors M, Steinberg SM, Rosenberg SA, Marincola FM (1999) Increased vaccine-specific T-cell frequency after peptide-based vaccination correlates with increased susceptibility to in vitro stimulation but does not lead to tumor regression. J Immunol 163:6292–6300PubMed

Parmiani G, Castelli C, Dalerba P, Mortarini R et al (2002) Cancer immunotherapy with peptide-based vaccines: what have we achieved? where are we going? JNCI 94:805–818CrossRefPubMed

Hoffman TK, Donnenberg AD, Finkelstein SD, Donnenberg VS, Friebe-Hoffman F, Myers EN, Appella E, DeLeo AB, Whiteside TL (2002) Frequencies of tetramer+ T cells specific for the wild-type sequence p53_264–272 peptide in the circulations of patients with head and neck cancer. Cancer Res 62:3521–3529PubMed

Letsch A, Keilholz U, Schadendorf D, Nagorsen D, Schmittel A, Thiel E, Scheibenbogen C (2000) High frequencies of circulating melanoma-reactive CD8+ T cells in patients with advanced melanoma. Int J Cancer 87:659–664CrossRefPubMed

Whiteside TL (1994) Tumor-infiltrating lymphocytes in human solid tumors. Immunol Ser 61:137–148PubMed

Whiteside, TL, Parmiani G (1994) Tumor-infiltrating lymphocytes: their phenotype, function and clinical use. Cancer Immunol Immunother 39:15–21CrossRefPubMed

Saito T, Dworacki G, Gooding W, Lotze MT, Whiteside TL (2000) Spontaneous apoptosis of CD8+ T lymphocytes in peripheral blood of patients with advanced melanoma. Clin Cancer Res 6:1351–1364PubMed

Whiteside TL, Rabinowich H (1998) The role of Fas/FasL in immunosuppression induced by human tumors. Cancer Immunol Immunother 46:175–184PubMed

Uzzo RG, Clark PE, Rayman P, Bloom T, Rybicki L, Novick AC, Bukowski RM, Finke JH (1999) Alterations in NFκB activation in T lymphocytes of patients with renal cell carcinoma. JNCI 91:718–721CrossRefPubMed

10.

Gastman BR, Atarashi Y, Reichert TE, Saito T, Balkir L, Rabinowich H, Whiteside TL (1999) Fas ligand is expressed on human squamous cell carcinomas of the head and neck and it promotes apoptosis of T lymphocytes. Cancer Res 59:5356–5364PubMed

11.

Reichert TE, Strauss L, Wagner EM, Gooding W, Whiteside TL (2002) Signaling abnormalities and reduced proliferation of circulating and tumor-infiltrating lymphocytes in patients with oral carcinoma. Clin Cancer Res 8:3137–3145PubMed

12.

O’Connell J, O’Sullivan GD, Collins JK et al (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184:1075–1082PubMed

13.

Hoffmann TK, Dworacki G, Meidenbauer N, Gooding W, Johnson JT, Whiteside TL (2002) Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res 8:2553–2562PubMed

14.

Whiteside TL (2002) Apoptosis of immune cells in the tumor microenvironment and peripheral circulation of patients with cancer: implications for immunotherapy. Vaccine 20:A46–A51CrossRefPubMed

15.

Kersh EN, Shaw AS, Allen PM (1998) Fidelity of T cell activation through multistep T cell receptor ζ phosphorylation. Science 281:572–575CrossRefPubMed

16.

Valitutti S, Muller S, Salio M, Lanzavecchia A (1997) Degradation of T cell receptor (TCR)-CD3-ζ complexes after antigenic stimulation. J Exp Med 185:1859–1864CrossRefPubMed

17.

Stefanova I, Saville MW, Peters C, Cleghorn FR, Schwartz D, Venzon DF, Weinhold KJ, Jack N, Bartholomew C, Blattner WA, Yarchoan R, Bolen JB, Horak ID (1996) HIV infection-induced posttranslational modification of T cell signaling molecules associated with disease progression. J Clin Invest 98:1290–1297PubMed

18.

Zea AH, Ochoa MT, Ghosh P, Longo DL, Alvord WG, Valderrama L, Falabella R, Harvey LK, Saravia N, Moreno LH, Ochoa AC (1998) Changes in expression of signal transduction proteins in T lymphocytes of patients with leprosy. Infect Immun 66:499PubMed

19.

Liossis SN, Ding XZ, Dennis GJ, Tsokos GC (1998) Altered pattern of TCR/CD3-mediated protein-tyrosylphosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain. J Clin Invest 101:1448–1457PubMed

20.

Loeffler CM, Smyth MJ, Longo DL, Kopp WC, Harvery LK, Tribble HR, Tase JE, Urba WJ, Leonard AS, Young HA, Ochoa AC (1992) Immunoregulation in cancer-bearing hosts. Down-regulation of gene expression and cytotoxic function in CD8+ T cells. J Immunol 149:949–956PubMed

21.

Mizogushi H, O’Shea JJ, Longo DL, Loeffler CM, McVicar DW, Ochoa AC (1992) Alteration in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258:1975–1978

22.

Lai P, Rabinowich H, Crowley-Nowick PA, Bell MC, Mantovani G, Whiteside TL (1996) Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin Cancer Res 2:161–173PubMed

23.

Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR, Wiltrout RH, O’Shea JJ, Kudoh S, Klein E, Bukowski RM, Ochoa AC (1993) Loss of T-cell receptor chain and p56^lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 53:5613–5616PubMed

24.

Nakagomi H, Petersson M, Magnusson I, Juhlin C, Matsuda M, Mellstedt H, Taupin J-L, Vivier E, Anderson P, Kiessling R (1993) Decreased expression of the signal-transducing ζ chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer Res 53:5610–5612PubMed

25.

Matsuda M, Petersson M, Lenke R, Taupin J-L, Magnusson I, Mellstedt H, Anderson P, Kiessling R (1995) Alterations in the signal-transducing molecules of T cells and NK cells in colorectal tumor-infiltrating, gut mucosal and peripheral lymphocytes: correlation with the stage of the disease. Int J Cancer 61:765–772PubMed

26.

Healy CG, Simons JW, Carducci MA, DeWeese TL, Bartkowski M, Tong KP, Bolton WE (1998) Impaired expression and function of signal-transducing zeta chains in peripheral T cells and natural killer cells in patients with prostate cancer. Cytometry 32:109–119CrossRefPubMed

27.

Aoe T, Okamoto Y, Saito T (1995) Activated macrophages induce structural abnormalities of the T cell receptor-CD3 complex. J Exp Med 181:1881–1886PubMed

28.

Reichert TE, Day R, Wagner EM, Whiteside TL (1998) Absent or low expression of the ζ chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma. Cancer Res 58:5344–5347PubMed

29.

Zea AH, Brendan CD, Longo DL, Alvord WG, Strobl SL, Mizoguchi H, Creekmore SP, O’Shea JJ, Powers GC, Urba WJ, Ochoa AC (1995) Alterations in T cell receptor and signal transduction molecules in melanoma patients. Clin Cancer Res 1:1327–1335PubMed

30.

Kuss I, Saito T, Johnson JT, Whiteside TL (1999) Clinical significance of decreased ζ chain expression in peripheral blood lymphocytes of patients with head and neck cancer. Clin Cancer Res 5:329–334PubMed

31.

Dworacki G, Meidenbauer N, Kuss I, Hoffmann TK, Gooding MS, Lotze M, Whiteside TL (2001) Decrease ζ chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patient with melanoma. Clin Cancer Res 7:947–957

32.

Reichert TE, Rabinowich H, Johnson JT, Whiteside TL (1998) Immune cells in the tumor microenvironment: mechanisms responsible for signaling and functional defects. J Immunother 21:295–306PubMed

33.

Whiteside TL (1999) Signaling defects in T lymphocytes of patients with malignancy (Symposium in writing). Cancer Immunol Immunother 48:346–352PubMed

34.

Rabinowich H, Suminami Y, Reichert TE, Crowley-Nowick P, Bell M, Edwards R, Whiteside TL (1996) Expression of cytokine genes or proteins and signaling molecules in lymphocytes associated with human ovarian carcinoma. Int J Cancer 68:276–284PubMed

35.

Rabinowich H, Reichert TE, Kashii Y, Bell MC, Whiteside TL (1998) Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells: implications for altered expression of TcR in tumor-associated lymphocytes. J Clin Invest 101:2579–2588PubMed

36.

Kuss I, Donnenberg A, Gooding W, Whiteside TL (2003) Effector CD8⁺CD45RO⁻CD27⁻ T cells have signaling defects in patients with head and neck cancer. Br J Cancer 88:223–230CrossRefPubMed

37.

Asselin-Paturel C, Echchakin H, Carayol G, Gay F, Opolon P, Grunenwald D, Chouaib S, Mami-Chouaib F (1998) Quantitative analysis of Th1, Th2 and TGF-β 1 cytokine expression in tumor, TIL and PBL of non-small lung cancer patients. Int J Cancer 77:7–12CrossRefPubMed

38.

Krishnan S, Farber DL, Tsokos GC (2003) T cell rewiring in differentiation and disease. J Immunol 171:3325–3331.PubMed

39.

Taylor DD, Bender DP, el-Taylor GEI, Stanson J, Whiteside TL (2001) Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients. Br J Cancer 84:1624–1629CrossRefPubMed

40.

Shurin GV, Shurin MR, Lotze MT, Barksdale EM (2001) Gangliosides mediate neuroblastoma-induced inhibition of dendritic cell generation. Cancer Res 61:363–369PubMed

41.

Esche C, Lokshin A, Shurin G, Gastman BR, Rabinowich H, Lotze MT, Shurin MR (1999) Tumors’ other immune targets: dendritic cells. J Leukoc Biol 66:336–344PubMed

42.

Shurin MR, Gabrilovich DI (2001) Regulation of dendritic cell system by tumor. Cancer Res Ther Control 11:65–78

43.

Allison JP, Hurwitz AA, Leach DR (1995) Manipulation of co-stimulatory signals to enhance antitumor T-cell responses. Curr Opin Immunol 7:682–686

44.

Krishnan S, Warke VG, Nambiar MP, Wong HK, Tsokos GC, Farber DL (2001) Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3 ζ expression. Blood 15:3851–3859CrossRef

45.

Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, Nakazawa T, Anderson P, Kiessling R (1996) Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing ζ molecules and inhibits tumor-specific T cell- and natural killer cell-mediated cytoxicity. Eur J Immunol 26:1308PubMed

46.

Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res 61:4756–4760PubMed

47.

Taheri F, Ochoa JB, Faghiri Z, Culotta K, Park HJ, Lan MS, Zea AH, Ochoa AC (2001) L-Arginine regulates the expression of the T-cell receptor zeta chain (CD3zeta) in Jurkat cells. Clin Cancer Res 7:958s-965sPubMed

48.

Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC (2002) Regulation of T cell receptor CD3zeta chain expression by L-arginine. J Biol Chem 277:21123–21129PubMed

49.

Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, Zanovello P, Segal DM (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168:689–695PubMed

50.

Zea AH, Atkins MB, DeSalvo J, Zwesdanjk K, Hernandez C, Rodriguez P, Zabaleta J, Ochoa AC (2003) Loss of T cell receptor CD3 ζ-chain by L-arginine depletion: role in renal cell carcinoma. J Immunother 26:S45

51.

Whiteside TL (2002) Tumor-induced death of immune cells: its mechanisms and consequences. Sem Cancer Biol 12:43–50CrossRef

52.

Atarashi Y, Kanaya H, Whiteside TL (1999) A modified JAM assay detects apoptosis induced in activated lymphocytes by FasL+ human adherent tumor cells. J Immunol Methods 233:179–182

53.

Gastman BR, Johnson DE, Whiteside TL, Rabinowich J (1999) Caspase-mediated degradation of TcR-ζ chain. Cancer Res 59:1422–1427PubMed

54.

Combadiere B, Freedman M, Chen L, Shores EW, Love P, Lenardo MJ (1996) Quantitative and qualitative contributions of the T-cell receptor ζ chain to mature T cell apoptosis. J Exp Med 183:2109–2117PubMed

55.

Schneider P, Holler N, Bodmer J, Hahne M, Frei K, Fontana A, Tschopp J (1998) 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 187:1205–1213PubMed

56.

Taylor DD, Gercel-Taylor C, Lyons KS, Stanson J, Whiteside TL (2003) T-cell apoptosis and suppression of TcR/CD3-ζ by FasL-containing membrane vesicles shed from ovarian tumors. Clin Cancer Res 9:5113–5119PubMed

57.

Andreola G, Rivoltini L, Castelli C, Huber V et al (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316CrossRefPubMed

58.

Kim J-W, Wieckowski E, Taylor D, Reichert T, Whiteside T (2003) FasL-containing microvesicles in the circulation of patients with cancer induce apoptosis of activated T lymphocytes. Abstr J Immunother 26:S44

59.

Schaeffer TM, Bell I, Fallert BA, Reinhart TA (2000) The T-cell receptor ζ contains two homologous domains with which similar immunodeficiency virus Nef interacts and mediates down-modulation. J Virol 74:3273–3283CrossRefPubMed

60.

Reichert TE, Scheuer C, Day R, Wagner W, Whiteside TL (2000) The number of intratumoral dendritic cells and ζ-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer 91:2136–2147CrossRef

61.

Cardi G, Heaney JA, Schned AR, Phillips DM, Branda MT, Ernstoff MS (1997) T-cell receptor ζ-chain expression on tumor-infiltrating lymphocytes from renal cell carcinoma. Cancer Res 57:3517–3519PubMed

62.

Kono K, Ressing ME, Brandt RMP, Melief CJM, Potkul RK, Andersson B, Petersson M, Kast WM, Kiessling R (1996) Decreased expression of signal-transducing ζ chain in peripheral T cells and natural killer cells in patients with cervical cancer. Clin Cancer Res 2:1825–1828PubMed

63.

Meidenbauer N, Gooding W, Spliter L, Harris D, Whiteside TL (2002) Recovery of ζ chain expression and changes in spontaneous IL-10 production after PSA-based vaccines in patients with prostate cancer. Br J Cancer 86:168–178CrossRefPubMed

64.

Tsukishiro T, Donnenberg AD, Whiteside TL (2003) Rapid turnover of the CD8+CD28- T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol Immunother 52:599–607CrossRefPubMed

65.

Kuss I, Rabinowich H, Gooding W, Edwards R, Whiteside TL (2002) Expression of ζ in T cells prior to IL-2 therapy as a predictor of response and survival in patients with ovarian carcinoma. Cancer Biother Radiopharmaceuticals 17:631–640CrossRef

66.

Rabinowich H, Banks M, Reichert TE, Logan TF, Kirkwood JM, Whiteside TL (1996) Expression and activity of signaling molecules in T lymphocytes obtained from patients with metastatic melanoma before and after interleukin 2 therapy. Clin Cancer Res 2:1263–1272PubMed

67.

Whiteside TL, Gooding W, Elder E, Stover L, Glaspy J, McMasters K, Deisseroth A, Hellstrand K, Naredi P, Gehlsen KR, O’Day SJ, Agarwala SS (2002) Immunomodulatory effects of combination therapy with histamine dihydrochloride and interleukin-2 during a phase II study in stage IV melanoma. Abstract of the 17th annual scientific meeting of the Society for Biological Therapy, La Jolla, CA

68.

Bukowski RM, Rayman P, Uzzo R, Bloom T, Sandstrom K, Peereboom D, Olencki T, Budd GT, McLain D, Elson P, Novick A, Finke JH (1998) Signal transduction abnormalities in T lymphocytes from patients with advanced renal carcinoma: clinical relevance and effects of cytokine therapy. Clin Cancer Res 4:2337–2347PubMed

69.

Gratama JW, Zea AH, Bolhuis RL, Ochoa AC (1999) Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy. Cancer Immunol Immunother 48:263–269PubMed

70.

Tartour E, Latour S, Mathiot C, Thiounn N, Mosser V, Joyeux I, D’Enghien CD, Lee R, Debre B, Fridman WH (1995) Variable expression of CD3-ζ chain in tumor-infiltrating lymphocytes (TIL) derived from renal-cell carcinoma: relationship with TIL phenotype and function. Int J Cancer 63:505–512PubMed

71.

Farace F, Angevin E, Vanderplancke J, Escudier B, Triebel F (1994) The decreased expression of CD3 ζ chains in cancer patients is not reversed by IL-2 administration. Int J Cancer 59:752–755PubMed

72.

Meidenbauer N, Harris DT, Spitler LE, Whiteside TL (2000) Generation of PSA-reactive effector cells after vaccination with a PSA-based vaccine in patients with prostate cancer. Prostate 43:88–100CrossRefPubMed

Titel: Down-regulation of ζ-chain expression in T cells: a biomarker of prognosis in cancer?
verfasst von: Theresa L. Whiteside
Publikationsdatum: 01.10.2004
Verlag: Springer-Verlag
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 10/2004
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-004-0521-0

Springer Medizin

Down-regulation of ζ-chain expression in T cells: a biomarker of prognosis in cancer?

Abstract

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