Defective antigen presentation resulting from impaired expression of costimulatory molecules in breast cancer

Previous experiments from our laboratory have shown that immune mechanisms aiming at the destruction of tumour cells including the recognition of target cells and their elimination via the expression of intercellular adhesion molecule‐1 (ICAM‐1; CD54), the production of tumour necrosis factor‐α (TNF‐α) by monocytes and appropriate function of lymphocyte subpopulations were defective in breast cancer. Previous observations were extended to assess expression levels and regulatory mechanisms of costimulatory molecules CD54, CD80 and CD86 on monocytes derived from patients with early breast cancer (EBC). In addition, antigen presentation by antigen‐presenting cells (APC) was analyzed within this context. We report that monocytes derived from patients with EBC exhibited significantly decreased expression levels of CD54 (p = 0.0002), CD80 (p = 0.009) and CD 86 (p = 0.002) compared with monocytes derived from healthy females. Simultaneously, lipopolysaccharide (LPS)‐induced TNF‐α production of monocytes was found to be defective in patients with EBC. Finally, T‐cell proliferation in response to tetanus toxoid (TT) was significantly decreased in patients with EBC compared with healthy control females (p < 0.0001). Furthermore, T‐cell proliferation in response to TT‐pulsed APC derived from healthy controls was significantly inhibited in the presence of anti‐CD54 and/or anti‐CD80 antibodies in a dose‐dependent manner, thus corroborating the necessity of the presence of CD54 and CD80 as costimulatory molecules in the present setting. We conclude that monocytes derived from patients with EBC showed a simultaneous defect of expression of CD54 and its regulation via TNF‐α, CD80 and CD86 as well as T‐cell proliferation following exposure to TT‐pulsed APC. Based upon these findings, it is speculated that defects in costimulatory molecule expression might contribute to tolerance of the immune system towards the presence of malignant cells in patients with EBC. Int. J. Cancer 88:239–244, 2000. © 2000 Wiley‐Liss, Inc.

[1]  J. Schlom,et al.  Construction and characterization of a recombinant vaccinia virus expressing murine intercellular adhesion molecule-1: induction and potentiation of antitumor responses. , 1997, Human gene therapy.

[2]  Kevin J. Tracey,et al.  Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia , 1987, Nature.

[3]  G. Gargano,et al.  Tumor necrosis factor and soluble interleukin-2 receptor: two immunological biomarkers in female neoplasms. , 1992, European journal of gynaecological oncology.

[4]  G Siegel,et al.  The role of the endothelium in inflammation and tumor metastasis. , 1997, International journal of microcirculation, clinical and experimental.

[5]  J. Sweetenham,et al.  Endothelial cell precursors are normal components of human umbilical cord blood , 1997, British journal of haematology.

[6]  R. Zeillinger,et al.  Reduced mitogenic stimulation of peripheral blood mononuclear cells as a prognostic parameter for the course of breast cancer: a prospective longitudinal study. , 1995, British Journal of Cancer.

[7]  E. Hofsli,et al.  A flow cytometric and immunofluorescence microscopic study of tumor necrosis factor production and localization in human monocytes. , 1989, Cellular immunology.

[8]  W. Fiers,et al.  Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane‐bound TNF in experimental cerebral malaria , 1997, European journal of immunology.

[9]  C. Wiltschke,et al.  Decreased expression of ICAM‐1 and its induction by tumor necrosis factor on breast‐cancer cells in vitro , 1997, International journal of cancer.

[10]  L. Turka,et al.  The role of T-cell costimulatory activation pathways in transplant rejection. , 1998, The New England journal of medicine.

[11]  M. Feldmann,et al.  TNFα Is an Effective Therapeutic Target for Rheumatoid Arthritis a , 1995, Annals of the New York Academy of Sciences.

[12]  R. Willemze,et al.  Induction of CD11a/leukocyte function antigen-1 and CD54/intercellular adhesion molecule-1 on hairy cell leukemia cells is accompanied by enhanced susceptibility to T-cell but not lymphokine-activated killer-cell cytotoxicity. , 1992, Blood.

[13]  H. Reiser,et al.  Role of the CTLA-4 receptor in t cell activation and immunity , 1998, Immunologic research.

[14]  R. Colman,et al.  Recombinant Tumor Necrosis Factor Receptor p75 Fusion Protein (TNFR:Fc) Alters Endotoxin-Induced Activation of the Kinin, Fibrinolytic, and Coagulation Systems in Normal Humans , 1998, Thrombosis and Haemostasis.

[15]  J. Belaiche,et al.  Tumour necrosis factor (TNF) gene polymorphism influences TNF‐α production in lipopolysaccharide (LPS)‐stimulated whole blood cell culture in healthy humans , 1998, Clinical and experimental immunology.

[16]  A. A. Brian,et al.  Contribution of lymphocyte function-associated-1/intercellular adhesion molecule-1 binding to the adhesion/signaling cascade of cytotoxic T lymphocyte activation , 1994, The Journal of experimental medicine.

[17]  D. Knight,et al.  An in vitro model of T cell activation by autologous cytomegalovirus (CMV)-infected human adult endothelial cells: contribution of CMV-enhanced endothelial ICAM-1. , 1998, Journal of immunology.

[18]  S. Ferrone,et al.  Clinical significance of alpha(v)beta3 integrin and intercellular adhesion molecule-1 expression in cutaneous malignant melanoma lesions. , 1997, Cancer research.

[19]  R. Burger,et al.  Role of 55- and 75-kDa tumor necrosis factor membrane receptors in the regulation of intercellular adhesion molecules-1 expression by HL-60 human promyelocytic leukemia cells in vitro. , 1993, Journal of immunology.

[20]  S. Papa,et al.  Inhibition of NK binding to K562 cells induced by MAb saturation of adhesion molecules on target membrane. , 1994, European journal of histochemistry : EJH.

[21]  D. Goeddel,et al.  Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. , 1994, Journal of immunology.

[22]  R. Donnelly,et al.  IFN-gamma priming of monocytes enhances LPS-induced TNF production by augmenting both transcription and MRNA stability. , 1995, Cytokine.

[23]  J. Pober,et al.  Tumor necrosis factor induction of endothelial cell surface antigens is independent of protein kinase C activation or inactivation. Studies with phorbol myristate acetate and staurosporine. , 1991, Journal of immunology.

[24]  J. Gribben,et al.  Transplantation of anergic histoincompatible bone marrow allografts. , 1999, The New England journal of medicine.

[25]  M. Mielke,et al.  Cytokines in the induction and expression of T‐cell‐mediated granuloma formation and protection in the murine model of listeriosis , 1997, Immunological reviews.

[26]  B. Naume,et al.  Immunoregulatory Effects of Cytokines on Natural Killer Cells , 1994, Scandinavian journal of immunology.

[27]  P. Lipsky,et al.  Enhancement of antigen- and mitogen-induced human T lymphocyte proliferation by tumor necrosis factor-alpha. , 1988, Journal of immunology.

[28]  T. Shimokama,et al.  Inhibition of mononuclear cell recruitment in aortic intima by treatment with anti-ICAM-1 and anti-LFA-1 monoclonal antibodies in hypercholesterolemic rats: implications of the ICAM-1 and LFA-1 pathway in atherogenesis. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[29]  J. D. Albert,et al.  Shock and tissue injury induced by recombinant human cachectin. , 1986, Science.

[30]  E. Kubista,et al.  Impaired production of tumor necrosis factor in breast cancer , 1990, Cancer.

[31]  P. Vassalli,et al.  The pathophysiology of tumor necrosis factors. , 1992, Annual review of immunology.

[32]  Arthur S Slutsky,et al.  Effects of the stress response in septic rats and LPS-stimulated alveolar macrophages: evidence for TNF-alpha posttranslational regulation. , 1996, American journal of respiratory and critical care medicine.

[33]  Soldano Ferrone,et al.  Clinical Significance of αvβ3 Integrin and Intercellular Adhesion Molecule-1 Expression in Cutaneous Malignant Melanoma Lesions , 1997 .

[34]  M. Cavazzana‐Calvo,et al.  Characteristics of antigen‐independent and antigen‐dependent interaction of dendritic cells with CD4+ T cells , 1995, Advances in experimental medicine and biology.

[35]  H. Feußner,et al.  Normal T lymphocyte and monocyte function after minimally invasive surgery , 1998, Surgical Endoscopy.

[36]  H. Reiser,et al.  Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases. , 1996, The New England journal of medicine.

[37]  C. Stewart,et al.  Tumor-Derived Factor Synergizes with IFN-γ and LPS, IL-2 or TNF-α to Promote Macrophage Synthesis of TNF-α and TNF Receptors for Autocrine Induction of Nitric Oxide Synthase and Enhanced Nitric Oxide-Mediated Tumor Cytotoxicity , 1995 .

[38]  J. Lunec,et al.  The TNF-ligand and receptor superfamilies: controllers of immunity and the Trojan horses of autoimmune disease? , 1996, Molecular aspects of medicine.

[39]  K. Ebnet,et al.  Borrelia burgdorferi activates nuclear factor-kappa B and is a potent inducer of chemokine and adhesion molecule gene expression in endothelial cells and fibroblasts. , 1997, Journal of immunology.

[40]  Guoyou Chen,et al.  Involvement of MHC class I molecule and ICAM-1 in the enhancement of adhesion and cytotoxic susceptibility to immune effector cells of tumor cells transfected with the interleukin (IL)-2, IL-4 or IL-6 gene , 1997, Journal of Cancer Research and Clinical Oncology.

[41]  B. Manger,et al.  [Regulation of T-cell activation by CD28 and CTLA-4]. , 1998, Medizinische Klinik.