B7-H1, a recently described member of the B7 family of costimulatory molecules, is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells. We report here that, except for cells of the macrophage lineage, normal human tissues do not express B7-H1. In contrast, B7-H1 is abundant in human carcinomas of lung, ovary and colon and in melanomas. The pro-inflammatory cytokine interferon-γ upregulates B7-H1 on the surface of tumor cell lines. Cancer cell–associated B7-H1 increases apoptosis of antigen-specific human T-cell clones in vitro, and the apoptotic effect of B7-H1 is mediated largely by one or more receptors other than PD-1. In addition, expression of B7-H1 on mouse P815 tumor increases apoptosis of activated tumor-reactive T cells and promotes the growth of highly immunogenic B7-1+ tumors in vivo. These findings have implications for the design of T cell–based cancer immunotherapy.
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Chambers, C.A. & Allison, J.P. Co-stimulation in T cell responses. Curr. Opin. Immunol. 9, 396–404 (1997).
Lenschow, D.J., Walunas, T.L. & Bluestone, J.A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).
Chen, L., Linsley, P.S. & Hellstrom, K.E. Costimulation of T cells for tumor immunity. Immunol. Today 14, 483–486 (1993).
Boise, L.H., Noel, P.J. & Thompson, C.B. CD28 and apoptosis. Curr. Opin. Immunol. 7, 620–625 (1995).
Watts, T.H. & DeBenedette, M.A. T cell co-stimulatory molecules other than CD28. Curr. Opin. Immunol. 11, 286–293 (1999).
Noel, P.J., Boise, L.H., Green, J.M. & Thompson, C.B. CD28 costimulation prevents cell death during primary T cell activation. J. Immunol. 157, 636–642 (1996).
Hurtado, J.C., Kim, Y.J. & Kwon, B.S. Signals through 4-1BB are costimulatory to previously activated splenic T cells and inhibit activation-induced cell death. J. Immunol. 158, 2600–2609 (1997).
Takahashi, C., Mittler, R.S. & Vella, A.T. 4-1BB is a bona fide CD8 T cell survival signal. J. Immunol. 162, 5037–5040 (1999).
Rogers, P.R., Song, J., Gramaglia, I., Killeen, N. & Croft, M. OX40 promotes bcl-xl and bcl-2 expression and is essential for long-term survival of CD4+ T cells. Immunity 15, 445–455 (2001).
Krummel, M.F. & Allison, J.P. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J. Exp. Med. 183, 2533–2540 (1996).
Walunas, T.L., Bakker, C.Y. & Bluestone, J.A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med. 183, 2541–2550 (1996).
Dong, H., Zhu, G., Tamada, K. & Chen, L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Med. 5, 1365–1369 (1999).
Tamura, H. et al. B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood 97, 1809–1816 (2001).
Freeman, G.J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif–carrying immunoreceptor. Immunity 11, 141–151 (1999).
Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor–deficient mice. Science 291, 319–322 (2001).
Rivoltini, L. et al. Quantitative correlation between HLA class I allele expression and recognition of melanoma cells by antigen-specific cytotoxic T lymphocytes. Cancer Res. 55, 3149–3157 (1995).
Nagata, S. & Golstein, P. The Fas death factor. Science 267, 1449–1456 (1995).
Jeremias, I., Herr, I., Boehler, T. & Debatin, K.M. TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur. J. Immunol. 28, 143–152 (1998).
Zhao, S. et al. Functional expression of TRAIL by lymphoid and myeloid tumour cells. Br. J. Haematol. 106, 827–832 (1999).
Lu, J. & Celis, E. Use of two predictive algorithms of the world wide web for the identification of tumor-reactive T-cell epitopes. Cancer Res. 60, 5223–5227 (2000).
Georgescu, L., Vakkalanka, R.K. Elkon, K.B. & Crow, M.K. Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas ligand. J. Clin. Invest. 100, 2622–2633 (1997).
Sykulev, Y. et al. High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins. Proc. Natl. Acad. Sci. USA 91, 11487–11491 (1994).
Tamada, K., Tamura, H., Flies, D.B., Fu, Y.X., Pease, L.R., Blazar, B.R. & Chen, L. Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. J. Clin. Invest. 109, 549–557 (2002).
Chen, L., McGowan, P., Ashe, S., Johnston, J., Li, Y., Hellstrom, I. & Hellstrom, K.E. Tumor immunogenicity determines the effect of B7 costimulation on T cell–mediated tumor immunity. J. Exp. Med. 179, 523–532 (1994).
Smyth, M.J., Godfrey, D.I. & Trapani, J.A. A fresh look at tumor immunosurveillance and immunotherapy. Nature Immunol. 2, 293–299 (2001).
Griffith, T.S, Brunner, T., Fletcher, S.M., Green, D.R. & Ferguson, T.A. Fas ligand–induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).
O'Connell, J., Bennett, M.W., O'Sullivan, G.C., Collins, J.K. & Shanahan, F. Fas counter-attack: the best form of tumor defense? Nature Med. 5, 267–268 (1999).
Strand, S. & Galle, P.R. Immune evasion by tumours: involvement of the CD95 (APO-1/Fas) system and its clinical implications. Mol. Med. Today 4, 63–68 (1998).
Chappell, D.B, Zaks, T.Z., Rosenberg, S.A. & Restifo, N.P. Human melanoma cells do not express Fas (Apo-1/CD95) ligand. Cancer Res. 59, 59–62 (1999).
Arai, H., Gordon, D., Nabel, E.G. & Nabel, G.J. Gene transfer of Fas ligand induces tumor regression in vivo. Proc. Natl. Acad. Sci. USA. 94, 13862–13867 (1997).
Nakashima, M., Sonoda, K. & Watanabe, K. Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated antigen, RCAS1. Nature Med. 5, 938–942 (1999).
Ishida, Y., Agata, Y., Shibahara, K. & Honjo, T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992).
Linsley, P.S., Greene, J.L., Brady, W., Bajorath, J., Ledbetter, J.A. & Peach, R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1, 793–801 (1994).
Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).
Finger, L.R. et al. G The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. Gene 197, 177–187 (1997).
Chapoval, A.I., Zhu, G. & Chen, L. Immunoglobulin fusion protein as a tool for evaluation of T-cell costimulatory molecules. Methods Mol. Med. 45, 247–255 (2000).
Kobayashi, H., Wood, M., Song, Y., Appella, E. & Celis, E. Defining promiscuous MHC class II helper T-cell epitopes for the HER2/neu tumor antigen. Cancer Res. 60, 5228–5236 (2000).
Yu, Z., Kryzer, T.J., Griesmann, G.E., Kim, K.K., Benarroch, E., & Lennon, V.A. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann. Neurol. 49, 146–154 (2001).
This study was supported in part by the US National Institutes of Health grants CA79915 and CA85721 (to L.C.), CA37343 (to V.A.L.), CA80782 and CA82677 (to E.C.) and CA15083 (Mayo Clinic Cancer Center). We thank L. Murphy for the processing of tissue samples; L.L. Hinkley for data processing; Z. Yu for facilitating a study on the expression of B7-H1 on a lung cancer line; H. Kobayashi for advice on T-cell culture; and K. Jensen for editing the manuscript. Some of the results presented in this paper (expression of B7-H1 in human tumor lines) were presented at a National Cancer Institute Symposium, 'Tumor escape from immune recognition: Molecular mechanism and functional significance', 22–23 August 1999, Baltimore, Maryland.
A patent application regarding the method to enhance immune responses by blockade of B7-H1 was filed before the publication.
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Dong, H., Strome, S., Salomao, D. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med 8, 793–800 (2002). https://doi.org/10.1038/nm730
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