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Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.

Wick M, Dubey P, Koeppen H, Siegel CT, Fields PE, Chen L, Bluestone JA, Schreiber H - J. Exp. Med. (1997)

Bottom Line: We find that the tumor expressed Ld in the T cell receptor transgenic mice but grew, while the Ld-positive skin was rejected.Thus, despite an abundance of antigen-specific T cells, the malignant tissue grew while normal tissue expressing the same epitopes was rejected.Expression of costimulatory molecules on the tumor cells after transfection and preimmunization by full-thickness skin grafts was required for rejection of a subsequent tumor challenge, but there was no detectable effect of active immunization once the tumor was established.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA. mwick@midway.uchicago.edu

ABSTRACT
One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen. An explanation for this phenomenon could be that different T cell clones react to the normal graft and the malignant cells, respectively, and only the tumor-reactive clonotypes may be affected by the growing tumor. To test this hypothesis, we used a T cell receptor transgenic mouse in which essentially all CD8(+) T cells are specific for a closely related set of self-peptides presented on the MHC class I molecule Ld. We find that the tumor expressed Ld in the T cell receptor transgenic mice but grew, while the Ld-positive skin was rejected. Thus, despite an abundance of antigen-specific T cells, the malignant tissue grew while normal tissue expressing the same epitopes was rejected. Therefore, systemic T cell exhaustion or anergy was not responsible for the growth of the antigenic cancer cells. Expression of costimulatory molecules on the tumor cells after transfection and preimmunization by full-thickness skin grafts was required for rejection of a subsequent tumor challenge, but there was no detectable effect of active immunization once the tumor was established. Thus, the failure of established tumors to attract and activate tumor-specific T cells at the tumor site may be a major obstacle for preventive or therapeutic vaccination against antigenic cancer.

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Expression of the costimulatory molecules B7-1 and CD48  by the Ld-positive AG104A tumor cells leads to slower tumor outgrowth  in naive TCR transgenic mice. AG104A cells expressing the costimulatory molecules B7-1 and CD48 (18) were transfected with an Ld cDNA  expression vector. The expression level of Ld, B7-1, and CD48 in these  triple transfected cells, named AG104ABC–Ld, is shown in A. To determine the effect of expression of B7-1 and CD48 on tumor cell outgrowth  (B), naive TCR transgenic mice were injected with either AG104A–Ld  cells (3 mice) or AG104ABC–Ld cells (11 mice). AG104ABC–Ld tumor  cells grew slower than AG104A–Ld tumor cells. Bars indicate the SEM.
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Figure 6: Expression of the costimulatory molecules B7-1 and CD48 by the Ld-positive AG104A tumor cells leads to slower tumor outgrowth in naive TCR transgenic mice. AG104A cells expressing the costimulatory molecules B7-1 and CD48 (18) were transfected with an Ld cDNA expression vector. The expression level of Ld, B7-1, and CD48 in these triple transfected cells, named AG104ABC–Ld, is shown in A. To determine the effect of expression of B7-1 and CD48 on tumor cell outgrowth (B), naive TCR transgenic mice were injected with either AG104A–Ld cells (3 mice) or AG104ABC–Ld cells (11 mice). AG104ABC–Ld tumor cells grew slower than AG104A–Ld tumor cells. Bars indicate the SEM.

Mentions: The above experiments showed that mice bearing early or late Ld-positive tumors can show specific immunity against Ld-positive skin tissue without detectable effects on tumor growth. Because skin tissue differs from tumor tissue in that it contains a high number of potent antigen-presenting cells (Langerhans cells) that express costimulatory molecules, we determined whether expression of costimulatory molecules by the growing tumor would suffice to activate the CD8+ T cells and result in tumor rejection. We introduced an Ld expression vector into AG104A cells already transfected to express B7-1 and CD48 (18; renamed AG104ABC cells). The expression level of Ld, B7-1 and CD48 in these triple transfectants (AG104ABC–Ld), also shown in Fig. 6 A, is 15-fold, 200-fold, and 11-fold above background, respectively. AG104ABC–Ld cells were sensitive to lysis in vitro by the anti-Ld CD8+ T cell clone 900-2 in a 4.5-h 51Cr release assay (see Fig. 4). However, 10 of the 11 anti-Ld transgenic mice failed to reject the challenge of AG104ABC-Ld tumor cells (tumor incidence 91%; Table 2). In nine of the mice, the outgrowth of AG104ABC–Ld was significantly slower as compared with tumor cells expressing only the Ld antigen, but no costimulatory molecules (Fig. 6 B). Nevertheless, the AG104ABC–Ld tumors grew out to kill the animals. An additional mouse showed a persistent nongrowing 1-mm3 firm nodule that contained AG104ABC–Ld tumor cells upon reisolation and FACS® staining with AG104A-specific and Ld-specific mAbs. Only one mouse rejected the tumor cell challenge completely. The untransfected tumor cells or those expressing only Ld or B7 and CD48 grew progressively in all of the mice (Table 2).


Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.

Wick M, Dubey P, Koeppen H, Siegel CT, Fields PE, Chen L, Bluestone JA, Schreiber H - J. Exp. Med. (1997)

Expression of the costimulatory molecules B7-1 and CD48  by the Ld-positive AG104A tumor cells leads to slower tumor outgrowth  in naive TCR transgenic mice. AG104A cells expressing the costimulatory molecules B7-1 and CD48 (18) were transfected with an Ld cDNA  expression vector. The expression level of Ld, B7-1, and CD48 in these  triple transfected cells, named AG104ABC–Ld, is shown in A. To determine the effect of expression of B7-1 and CD48 on tumor cell outgrowth  (B), naive TCR transgenic mice were injected with either AG104A–Ld  cells (3 mice) or AG104ABC–Ld cells (11 mice). AG104ABC–Ld tumor  cells grew slower than AG104A–Ld tumor cells. Bars indicate the SEM.
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Related In: Results  -  Collection

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Figure 6: Expression of the costimulatory molecules B7-1 and CD48 by the Ld-positive AG104A tumor cells leads to slower tumor outgrowth in naive TCR transgenic mice. AG104A cells expressing the costimulatory molecules B7-1 and CD48 (18) were transfected with an Ld cDNA expression vector. The expression level of Ld, B7-1, and CD48 in these triple transfected cells, named AG104ABC–Ld, is shown in A. To determine the effect of expression of B7-1 and CD48 on tumor cell outgrowth (B), naive TCR transgenic mice were injected with either AG104A–Ld cells (3 mice) or AG104ABC–Ld cells (11 mice). AG104ABC–Ld tumor cells grew slower than AG104A–Ld tumor cells. Bars indicate the SEM.
Mentions: The above experiments showed that mice bearing early or late Ld-positive tumors can show specific immunity against Ld-positive skin tissue without detectable effects on tumor growth. Because skin tissue differs from tumor tissue in that it contains a high number of potent antigen-presenting cells (Langerhans cells) that express costimulatory molecules, we determined whether expression of costimulatory molecules by the growing tumor would suffice to activate the CD8+ T cells and result in tumor rejection. We introduced an Ld expression vector into AG104A cells already transfected to express B7-1 and CD48 (18; renamed AG104ABC cells). The expression level of Ld, B7-1 and CD48 in these triple transfectants (AG104ABC–Ld), also shown in Fig. 6 A, is 15-fold, 200-fold, and 11-fold above background, respectively. AG104ABC–Ld cells were sensitive to lysis in vitro by the anti-Ld CD8+ T cell clone 900-2 in a 4.5-h 51Cr release assay (see Fig. 4). However, 10 of the 11 anti-Ld transgenic mice failed to reject the challenge of AG104ABC-Ld tumor cells (tumor incidence 91%; Table 2). In nine of the mice, the outgrowth of AG104ABC–Ld was significantly slower as compared with tumor cells expressing only the Ld antigen, but no costimulatory molecules (Fig. 6 B). Nevertheless, the AG104ABC–Ld tumors grew out to kill the animals. An additional mouse showed a persistent nongrowing 1-mm3 firm nodule that contained AG104ABC–Ld tumor cells upon reisolation and FACS® staining with AG104A-specific and Ld-specific mAbs. Only one mouse rejected the tumor cell challenge completely. The untransfected tumor cells or those expressing only Ld or B7 and CD48 grew progressively in all of the mice (Table 2).

Bottom Line: We find that the tumor expressed Ld in the T cell receptor transgenic mice but grew, while the Ld-positive skin was rejected.Thus, despite an abundance of antigen-specific T cells, the malignant tissue grew while normal tissue expressing the same epitopes was rejected.Expression of costimulatory molecules on the tumor cells after transfection and preimmunization by full-thickness skin grafts was required for rejection of a subsequent tumor challenge, but there was no detectable effect of active immunization once the tumor was established.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA. mwick@midway.uchicago.edu

ABSTRACT
One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen. An explanation for this phenomenon could be that different T cell clones react to the normal graft and the malignant cells, respectively, and only the tumor-reactive clonotypes may be affected by the growing tumor. To test this hypothesis, we used a T cell receptor transgenic mouse in which essentially all CD8(+) T cells are specific for a closely related set of self-peptides presented on the MHC class I molecule Ld. We find that the tumor expressed Ld in the T cell receptor transgenic mice but grew, while the Ld-positive skin was rejected. Thus, despite an abundance of antigen-specific T cells, the malignant tissue grew while normal tissue expressing the same epitopes was rejected. Therefore, systemic T cell exhaustion or anergy was not responsible for the growth of the antigenic cancer cells. Expression of costimulatory molecules on the tumor cells after transfection and preimmunization by full-thickness skin grafts was required for rejection of a subsequent tumor challenge, but there was no detectable effect of active immunization once the tumor was established. Thus, the failure of established tumors to attract and activate tumor-specific T cells at the tumor site may be a major obstacle for preventive or therapeutic vaccination against antigenic cancer.

Show MeSH
Related in: MedlinePlus