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ABSTRACT: Mature dendritic cells (DCs) are powerful antigen presenting cells that have the unique capacity to migrate to the T cell zone of draining lymph nodes after subcutaneous injection. Here we report that treatment of antigen-pulsed mature DCs with tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a TNF family member, before immunization enhances their adjuvant capacity and elicits improved T cell priming in vivo, such that both primary and memory T cell immune responses are enhanced. By enumerating migratory DCs in the draining lymph nodes and by studying their function in stimulating naive T cells, we show that one of the underlying mechanisms for enhanced T cell responses is an increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell areas of lymph nodes. These results suggest that the longevity and abundance of mature DCs at the site of T cell priming influence the strength of the DC-initiated T cell immunity in situ. Our findings have the potential to improve DC-based immunotherapy; i.e., the active immunization of humans with autologous DCs that have been pulsed with clinically significant antigens ex vivo.
Journal of Experimental Medicine 03/2000; 191(3):495-502. · 13.85 Impact Factor
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ABSTRACT: Tumors evade host immunity at both the induction and effector phases Most studies have focused on tumor evasion at the induction phase, and, due in part to poor antitumor CTL responses to most tumors, the mechanism for evasion of CTL effector function is less clear. Here we have taken advantage of the strong CTL responses to a costimulator B7-1-transfected tumor to study the mechanism for tumor evasion of preexisting host immunity. We have investigated six independent recurrent tumors isolated from mice that were challenged with and had rejected B7-1-transfected J558 (J558-B7) tumors. Because the mice had developed strong antitumor CTL responses, these recurrent tumors must have evaded preexisting antitumor CTLs. Indeed, whereas the parental J558-B7 cell line is efficiently lysed by the ex vivo tumor-infiltrating lymphocytes, all of the recurrent tumors are resistant to such lysis. Interestingly, the recurrent tumors can be divided into two groups. The group 1 tumors have vastly reduced levels of cell surface MHC class I with a concurrent reduction in the expression of multiple genes devoted to MHC class I antigen presentation. In contrast, the group 2 tumors have lost the expression of costimulatory molecule B7-1 while retaining cell surface MHC class I and expression of all antigen presentation genes studied. These results demonstrate that tumors can evade preexisting CTLs either by avoiding presentation of the tumor antigen or, surprisingly, by down-regulation of costimulatory molecules. The paradoxical requirements of both antigen and costimulatory molecules at the effector phase raised an interesting question on the nature of antitumor immunity.
Cancer Research 08/1999; 59(14):3461-7. · 7.86 Impact Factor
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ABSTRACT: Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical issue is whether unmutated tumor antigens are expressed in normal cells, and if so, whether such expression imposes special restrictions on cytotoxic T lymphocyte (CTL) responses. In this study, we use a transgenic approach to study the development and effector function of T cells specific for P1A, a prototypical unmutated tumor antigen. We report here that although P1A is expressed at low levels in normal tissues, including lymphoid tissues, the P1A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopoietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cells must have escaped clonal deletion due to low expression of P1A in the thymus. Interestingly, despite the fact that an overwhelming majority of T cells in the T cell receptor for antigen (TCR)-transgenic mice are specific for P1A, these mice are no more resistant to a P1A-expressing plasmocytoma than nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1(+) and B7-1(-) tumors, only B7-1(+) tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunotherapy.
Journal of Experimental Medicine 04/1999; 189(5):811-20. · 13.85 Impact Factor
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ABSTRACT: It is generally believed that CTLs mature in lymphoid organs and then migrate into target tissues to execute their effector functions. This notion, however, is based on studies using antigens that are readily localized in the lymphoid tissue, such as viruses and allogeneic transplants. The site for maturation of CTLs for nonmetastatic tumors has not been determined. Because nonmetastatic tumor cells are not localized in lymphoid tissues, it is questionable whether such tumors are efficient inducers of antitumor CTLs. Here, we report that a nonmetastatic B7+ plasmacytoma induces strong effector CTL response. Thus, it is possible to induce CTLs with strong ex vivo CTL activity in the absence of tumor metastasis. In addition, a detailed kinetic analysis of CD8 T cell recruitment and maturation of CTL activity suggests that antitumor CTLs mature within the tumor rather than in the lymphoid tissues. Interestingly, despite B7-1 expression on tumor cells, induction of effector CTLs also requires costimulation by B7 on host antigen-presenting cells. These findings have important implications for tumor gene therapy and for understanding the mechanism of CTL induction in vivo.
Cancer Research 09/1998; 58(15):3376-84. · 7.86 Impact Factor
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ABSTRACT: Whether tumors of different lineages share common Ags is a critical issue for understanding anti-tumor immune responses and for designing Ag-specific tumor immunotherapy. Because of lack of cross-protection among individually derived tumors, it has been proposed that tumor Ags are specific for individual tumors. Here we show that lack of cross-protection is not due to lack of a shared tumor Ag. Thus, a plasmocytoma J558 transfected with the costimulatory molecule B7 activates a cross-reactive CTL response in vivo. The major Ag recognized by the cross-reactive CTL is P1A, which is expressed in mastocytoma P815, plasmocytoma J558, and fibrosarcoma Meth A. Surprisingly, no significant cross-protection can be detected among P1A-expressing tumors after immunization with either P1A-expressing or B7-transfected P815 cells. Our results demonstrate that multiple lineages of tumors are not cross-protected even though they share a tumor Ag that can be recognized by CTL. These results have important implications for tumor immunotherapy.
The Journal of Immunology 01/1996; 155(11):5323-9. · 5.79 Impact Factor
