The tumor barrier comprised of nonantigenic stromal cells may contribute to the failure of tumor rejection. The tumor-necrosis factor superfamily member LIGHT (also known as TNFSF-14) is a ligand of stromal cell–expressed lymphotoxin-β receptor and T cell–expressed herpes viral entry mediator (HVEM). Here we show that forced expression of LIGHT in the tumor environment induces a massive infiltration of naive T lymphocytes that correlates with an upregulation of both chemokine production and expression of adhesion molecules. Activation of these infiltrating T cells, possibly through HVEM, leads to the rejection of established, highly progressive tumors at local and distal sites. Our study indicates that targeting the tumor barrier may be an effective strategy for cancer immunotherapy.
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Boon, T. & van der Bruggen, P. Human tumor antigens recognized by T lymphocytes. J. Exp. Med. 183, 725–729 (1996).
Rosenberg, S.A. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10, 281–287 (1999).
Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738 (2002).
Berzofsky, J.A., Ahlers, J.D. & Belyakov, I.M. Strategies for designing and optimizing new generation vaccines. Nat. Rev. Immunol. 1, 209–219 (2001).
Pardoll, D.M. Spinning molecular immunology into successful immunotherapy. Nat. Rev. Immunol. 2, 227–238 (2002).
Chambers, C.A., Kuhns, M.S., Egen, J.G. & Allison, J.P. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu. Rev. Immunol. 19, 565–594 (2001).
Terabe, M. et al. NKT cell–mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat. Immunol. 1, 515–520 (2000).
Ochsenbein, A.F. et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc. Natl. Acad. Sci. USA 96, 2233–2238 (1999).
Singh, S., Ross, S.R., Acena, M., Rowley, D.A. & Schreiber, H. Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J. Exp. Med. 175, 139–146 (1992).
Perdrizet, G.A. et al. Animals bearing malignant grafts reject normal grafts that express through gene transfer the same antigen. J. Exp. Med. 171, 1205–1220 (1990).
Sarma, S. et al. Cytotoxic T lymphocytes to an unmutated tumor rejection antigen P1A: normal development but restrained effector function in vivo . J. Exp. Med. 189, 811–820 (1999).
Wick, M. et al. Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. J. Exp. Med. 186, 229–238 (1997).
Hanson, H.L. et al. Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13, 265–276 (2000).
Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
Rosenberg, S.A. Progress in the development of immunotherapy for the treatment of patients with cancer. J. Intern. Med. 250, 462–475 (2001).
Lee, K.H. et al. 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, 6292–6300 (1999).
Mauri, D.N. et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).
Ngo, V.N. et al. Lymphotoxin α/β and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189, 403–412 (1999).
Wang, J. et al. The complementation of lymphotoxin deficiency with LIGHT, a newly discovered TNF family member, for the restoration of secondary lymphoid structure and function. Eur. J. Immunol. 32, 1969–1979 (2002).
Ueno, T. et al. Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus. Immunity 16, 205–218 (2002).
Gunn, M.D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).
Tamada, K. et al. Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway. Nat. Med. 6, 283–289 (2000).
Dranoff, G. et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc. Natl. Acad. Sci. USA 90, 3539–3543 (1993).
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. et al. Tumor immunogenicity determines the effect of B7 costimulation on T cell-mediated tumor immunity. J. Exp. Med. 179, 523–532 (1994).
Montgomery, R.I., Warner, M.S., Lum, B.J. & Spear, P.G. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87, 427–436 (1996).
Kwon, B.S. et al. A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation. J. Biol. Chem. 272, 14272–14276 (1997).
Harrop, J.A. et al. Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines. J. Immunol. 161, 1786–1794 (1998).
Fu, Y.X. & Chaplin, D.D. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17, 399–433 (1999).
Cyster, J.G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).
Farber, J.M. Mig and IP-10: CXC chemokines that target lymphocytes. J. Leukoc. Biol. 61, 246–257 (1997).
Kang, H.S. et al. Signaling via LTβR on the lamina propria stromal cells of the gut is required for IgA production. Nat. Immunol. 3, 576–582 (2002).
Yu, P., Spiotto, M.T., Lee, Y., Schreiber, H. & Fu, Y.X. Complementary role of CD4+ T cells and secondary lymphoid tissues for cross-presentation of tumor antigen to CD8+ T cells. J. Exp. Med. 197, 985–995 (2003).
Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8+ T cell subsets. Nat. Immunol. 4, 225–234 (2003).
Chen, L. Immunological ignorance of silent antigens as an explanation of tumor evasion. Immunol. Today 19, 27–30 (1998).
Ochsenbein, A.F. et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction. Nature 411, 1058–1064 (2001).
Spiotto, M.T. et al. Increasing tumor antigen expression overcomes 'ignorance' to solid tumors via crosspresentation by bone marrow–derived stromal cells. Immunity 17, 737–747 (2002).
Schrama, D. et al. Targeting of lymphotoxin-α to the tumor elicits an efficient immune response associated with induction of peripheral lymphoid-like tissue. Immunity 14, 111–121 (2001).
Sharma, S. et al. Secondary lymphoid tissue chemokine mediates T cell–dependent antitumor responses in vivo. J. Immunol. 164, 4558–4563 (2000).
Bai, X.F. et al. On the site and mode of antigen presentation for the initiation of clonal expansion of CD8 T cells specific for a natural tumor antigen. Cancer Res. 61, 6860–6867 (2001).
Wang, J. et al. The regulation of T cell homeostasis and autoimmunity by T cell–derived LIGHT. J. Clin. Invest. 108, 1771–1780 (2001).
Sharma, S. et al. SLC/CCL21-mediated antitumor responses require IFNγ, MIG/CXCL9 and IP-10/CXCL10. Mol. Cancer 2, 22 (2003).
Zhai, Y. et al. LIGHT, a novel ligand for lymphotoxin β receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer. J. Clin. Invest. 102, 1142–1151 (1998).
Harrop, J.A. et al. Herpesvirus entry mediator ligand (HVEM-L), a novel ligand for HVEM/TR2, stimulates proliferation of T cells and inhibits HT29 cell growth. J. Biol. Chem. 273, 27548–27556 (1998).
Browning, J.L. et al. Signaling through the lymphotoxin β receptor induces the death of some adenocarcinoma tumor lines. J. Exp. Med. 183, 867–878 (1996).
Ward, P.L., Koeppen, H., Hurteau, T. & Schreiber, H. Tumor antigens defined by cloned immunological probes are highly polymorphic and are not detected on autologous normal cells. J. Exp. Med. 170, 217–232 (1989).
Yu, P. et al. B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion. J. Immunol. 168, 5117–5123 (2002).
Wu, Q. et al. The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J. Exp. Med. 190, 629–638 (1999).
Hathcock, K.S. T cell depletion by cytotoxic elimination. in Current Protocols in Immunology (Coligan, J.E. et al.) 3.4.1–3.4.3 (Wiley, New York, 1991).
We thank L. Chen for advice and support, and M. Spiotto and J. Lo for their technical assistance. This work was supported by grants from the NIH (R01-HD37104, R01-DK58897 and P01-CA09296-01). P.Y. is a recipient of an NIH training grant (5T32DK07074).
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