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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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An anti-Ld–specific CD8+ T cell clone from TCR transgenic  mice has cytolytic activity against AG104A–Ld and AG104ABC–Ld tumor cells in vitro. The CD8+ T cell clone 900-2 derived from the 2C  TCR transgenic mice specifically recognizes and lyses AG104A–Ld and  AG104ABC–Ld tumor cells, but not AG104A–wt tumor cells in a 4.5-h  51Cr release assay in vitro.
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Figure 4: An anti-Ld–specific CD8+ T cell clone from TCR transgenic mice has cytolytic activity against AG104A–Ld and AG104ABC–Ld tumor cells in vitro. The CD8+ T cell clone 900-2 derived from the 2C TCR transgenic mice specifically recognizes and lyses AG104A–Ld and AG104ABC–Ld tumor cells, but not AG104A–wt tumor cells in a 4.5-h 51Cr release assay in vitro.

Mentions: Because the anti-Ld TCR transgenic mice failed to reject Ld-positive tumor cells, but rejected Ld-positive skin grafts, we determined whether the tumor cells could be lysed in vitro by Ld-specific T cells expressing the 2C clonotype. Fig. 4 shows that the Ld-transfected AG104A tumor cells were lysed specifically in a 4.5-h 51Cr release assay by the anti-Ld CD8+ cytolytic T cell clone 900-2 derived from the transgenic mice. This result showed that the failure of the AG104A–Ld tumor cells to be rejected by the C3H × 2C mice was not because the tumor cells were resistant to lysis by the transgenic T cells.


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)

An anti-Ld–specific CD8+ T cell clone from TCR transgenic  mice has cytolytic activity against AG104A–Ld and AG104ABC–Ld tumor cells in vitro. The CD8+ T cell clone 900-2 derived from the 2C  TCR transgenic mice specifically recognizes and lyses AG104A–Ld and  AG104ABC–Ld tumor cells, but not AG104A–wt tumor cells in a 4.5-h  51Cr release assay in vitro.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198977&req=5

Figure 4: An anti-Ld–specific CD8+ T cell clone from TCR transgenic mice has cytolytic activity against AG104A–Ld and AG104ABC–Ld tumor cells in vitro. The CD8+ T cell clone 900-2 derived from the 2C TCR transgenic mice specifically recognizes and lyses AG104A–Ld and AG104ABC–Ld tumor cells, but not AG104A–wt tumor cells in a 4.5-h 51Cr release assay in vitro.
Mentions: Because the anti-Ld TCR transgenic mice failed to reject Ld-positive tumor cells, but rejected Ld-positive skin grafts, we determined whether the tumor cells could be lysed in vitro by Ld-specific T cells expressing the 2C clonotype. Fig. 4 shows that the Ld-transfected AG104A tumor cells were lysed specifically in a 4.5-h 51Cr release assay by the anti-Ld CD8+ cytolytic T cell clone 900-2 derived from the transgenic mice. This result showed that the failure of the AG104A–Ld tumor cells to be rejected by the C3H × 2C mice was not because the tumor cells were resistant to lysis by the transgenic T cells.

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