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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: One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen.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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Anti-Ld TCR transgenic mice reject Ld-positive skin, but do  not reject a simultaneous challenge with Ld-expressing tumor cells. Two  TCR transgenic mice were transplanted with full-thickness Ld-positive  skin from a BALB/c mouse and concurrently received subcutaneous injections of AG104A–wt cells and AG104A–Ld cells on opposite flanks.  Whereas both mice rejected the skin graft at day 13 after transplantation  (see Table 1), both wt and Ld-expressing tumors grew progressively (A  and C). Bars indicate the SEM. The outgrowth of AG104A–Ld was not  due to antigen loss, because tumor cells reisolated on day 24 still stained  positive for Ld in a FACS® analysis (B and D). Shaded curve, anti-Ld staining, unshaded curve, staining with goat anti–mouse FITC secondary antibody alone.
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Figure 5: Anti-Ld TCR transgenic mice reject Ld-positive skin, but do not reject a simultaneous challenge with Ld-expressing tumor cells. Two TCR transgenic mice were transplanted with full-thickness Ld-positive skin from a BALB/c mouse and concurrently received subcutaneous injections of AG104A–wt cells and AG104A–Ld cells on opposite flanks. Whereas both mice rejected the skin graft at day 13 after transplantation (see Table 1), both wt and Ld-expressing tumors grew progressively (A and C). Bars indicate the SEM. The outgrowth of AG104A–Ld was not due to antigen loss, because tumor cells reisolated on day 24 still stained positive for Ld in a FACS® analysis (B and D). Shaded curve, anti-Ld staining, unshaded curve, staining with goat anti–mouse FITC secondary antibody alone.

Mentions: Whereas AG104A–Ld tumor cells can be lysed by preactivated cytolytic T cells in vitro, the activation of the anti-Ld T cells by the tumor in vivo may be inefficient. Rejection of full-thickness skin grafts is a powerful immunization procedure, probably owing to the abundance of dendritic cells (Langerhans cells) in the skin. Therefore, to determine whether activation of the T cells by skin graft rejection would also lead to rejection of the tumor, we inoculated TCR transgenic mice with Ld-positive tumor cells at the same time that we transplanted Ld-positive skin onto these mice. Mice rejected the skin grafts at day 13 after transplantation; however, there was no effect on the growth of the Ld-positive tumors that were already well established at this time (Fig. 5, A and C). The outgrowth of the Ld-positive tumors was not due to antigen loss, because FACS® analysis of the tumors reisolated at day 24 showed no loss or decrease in Ld expression (Fig. 5, B and D).


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)

Anti-Ld TCR transgenic mice reject Ld-positive skin, but do  not reject a simultaneous challenge with Ld-expressing tumor cells. Two  TCR transgenic mice were transplanted with full-thickness Ld-positive  skin from a BALB/c mouse and concurrently received subcutaneous injections of AG104A–wt cells and AG104A–Ld cells on opposite flanks.  Whereas both mice rejected the skin graft at day 13 after transplantation  (see Table 1), both wt and Ld-expressing tumors grew progressively (A  and C). Bars indicate the SEM. The outgrowth of AG104A–Ld was not  due to antigen loss, because tumor cells reisolated on day 24 still stained  positive for Ld in a FACS® analysis (B and D). Shaded curve, anti-Ld staining, unshaded curve, staining with goat anti–mouse FITC secondary antibody alone.
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Figure 5: Anti-Ld TCR transgenic mice reject Ld-positive skin, but do not reject a simultaneous challenge with Ld-expressing tumor cells. Two TCR transgenic mice were transplanted with full-thickness Ld-positive skin from a BALB/c mouse and concurrently received subcutaneous injections of AG104A–wt cells and AG104A–Ld cells on opposite flanks. Whereas both mice rejected the skin graft at day 13 after transplantation (see Table 1), both wt and Ld-expressing tumors grew progressively (A and C). Bars indicate the SEM. The outgrowth of AG104A–Ld was not due to antigen loss, because tumor cells reisolated on day 24 still stained positive for Ld in a FACS® analysis (B and D). Shaded curve, anti-Ld staining, unshaded curve, staining with goat anti–mouse FITC secondary antibody alone.
Mentions: Whereas AG104A–Ld tumor cells can be lysed by preactivated cytolytic T cells in vitro, the activation of the anti-Ld T cells by the tumor in vivo may be inefficient. Rejection of full-thickness skin grafts is a powerful immunization procedure, probably owing to the abundance of dendritic cells (Langerhans cells) in the skin. Therefore, to determine whether activation of the T cells by skin graft rejection would also lead to rejection of the tumor, we inoculated TCR transgenic mice with Ld-positive tumor cells at the same time that we transplanted Ld-positive skin onto these mice. Mice rejected the skin grafts at day 13 after transplantation; however, there was no effect on the growth of the Ld-positive tumors that were already well established at this time (Fig. 5, A and C). The outgrowth of the Ld-positive tumors was not due to antigen loss, because FACS® analysis of the tumors reisolated at day 24 showed no loss or decrease in Ld expression (Fig. 5, B and D).

Bottom Line: One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen.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