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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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AG104A–Ld tumor cells grow progressively and retain Ld expression in normal C3H × C57BL/6 mice and anti-Ld TCR transgenic  mice. AG104A–Ld cells were injected subcutaneously into the flanks of  four normal C3H × C57BL/6 mice and five anti-Ld C3H × 2C TCR  transgenic mice (A) or two nude mice and three anti-Ld C3H × 2C  TCR transgenic mice (B). Tumors grew out in all types of mice. Bars indicate the SEM. FACS® analysis of AG104A–Ld tumor cells reisolated at  day 27 from a nontransgenic mouse (C) or at day 33 from a TCR transgenic mouse (D) showed that antigen expression was retained in the  course of tumor growth. Shaded curve, anti-Ld staining; unshaded curve,  staining with goat anti–mouse FITC secondary antibody alone.
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Figure 2: AG104A–Ld tumor cells grow progressively and retain Ld expression in normal C3H × C57BL/6 mice and anti-Ld TCR transgenic mice. AG104A–Ld cells were injected subcutaneously into the flanks of four normal C3H × C57BL/6 mice and five anti-Ld C3H × 2C TCR transgenic mice (A) or two nude mice and three anti-Ld C3H × 2C TCR transgenic mice (B). Tumors grew out in all types of mice. Bars indicate the SEM. FACS® analysis of AG104A–Ld tumor cells reisolated at day 27 from a nontransgenic mouse (C) or at day 33 from a TCR transgenic mouse (D) showed that antigen expression was retained in the course of tumor growth. Shaded curve, anti-Ld staining; unshaded curve, staining with goat anti–mouse FITC secondary antibody alone.

Mentions: We have shown previously that PRO4L fibrosarcoma cells transfected to express certain alloantigens can grow progressively in immunocompetent mice, while normal skin transplants expressing the same alloantigens are rejected (12, 25). To determine whether this characteristic is shared by other tumor cell lines, we transfected a poorly immunogenic C3H fibrosarcoma that arose spontaneously in an aging mouse with the MHC class I alloantigen Ld. The transfected AG104A tumor cells (AG104A–Ld) expressed Ld at a level ∼40-fold above background as measured by flow cytometry (Fig. 1 A). Nevertheless all of the C3H × C57BL/6 F1 mice developed progressively growing lethal, antigen-positive tumors when injected subcutaneously with AG104A–Ld tumor cells. (Fig. 2 A). The tumor also grew progressively in C3H/HeN mice (data not shown). We reasoned that the precursor frequency of Ld-specific T cells in these mice may be too low to match the rapid growth of the Ld-expressing tumor cells. Therefore, AG104A–Ld tumor cells were injected into C3H × 2C anti-Ld TCR transgenic mice (13) in which all CD8+ T cells express the TCR 2C (see Fig. 1 B) that recognizes the Ld antigen in association with a set of closely related natural self-peptides (14, 15). Surprisingly, all of the transgenic mice developed lethal AG104A–Ld tumors despite the predominance of the anti-Ld T cells. In addition, the rate of tumor growth in transgenic mice was unaffected by the presence of the anti-Ld T cells because similar rates of growth were also observed in nontransgenic mice (Fig. 2 A) and nude mice (Fig. 2 B). Reisolation of the AG104A–Ld tumors showed that the expression of the Ld antigen was retained in vivo in the nontransgenic (Fig. 2 C) as well as in the transgenic mice (Fig. 2 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)

AG104A–Ld tumor cells grow progressively and retain Ld expression in normal C3H × C57BL/6 mice and anti-Ld TCR transgenic  mice. AG104A–Ld cells were injected subcutaneously into the flanks of  four normal C3H × C57BL/6 mice and five anti-Ld C3H × 2C TCR  transgenic mice (A) or two nude mice and three anti-Ld C3H × 2C  TCR transgenic mice (B). Tumors grew out in all types of mice. Bars indicate the SEM. FACS® analysis of AG104A–Ld tumor cells reisolated at  day 27 from a nontransgenic mouse (C) or at day 33 from a TCR transgenic mouse (D) showed that antigen expression was retained in the  course of tumor growth. Shaded curve, anti-Ld staining; unshaded curve,  staining with goat anti–mouse FITC secondary antibody alone.
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Figure 2: AG104A–Ld tumor cells grow progressively and retain Ld expression in normal C3H × C57BL/6 mice and anti-Ld TCR transgenic mice. AG104A–Ld cells were injected subcutaneously into the flanks of four normal C3H × C57BL/6 mice and five anti-Ld C3H × 2C TCR transgenic mice (A) or two nude mice and three anti-Ld C3H × 2C TCR transgenic mice (B). Tumors grew out in all types of mice. Bars indicate the SEM. FACS® analysis of AG104A–Ld tumor cells reisolated at day 27 from a nontransgenic mouse (C) or at day 33 from a TCR transgenic mouse (D) showed that antigen expression was retained in the course of tumor growth. Shaded curve, anti-Ld staining; unshaded curve, staining with goat anti–mouse FITC secondary antibody alone.
Mentions: We have shown previously that PRO4L fibrosarcoma cells transfected to express certain alloantigens can grow progressively in immunocompetent mice, while normal skin transplants expressing the same alloantigens are rejected (12, 25). To determine whether this characteristic is shared by other tumor cell lines, we transfected a poorly immunogenic C3H fibrosarcoma that arose spontaneously in an aging mouse with the MHC class I alloantigen Ld. The transfected AG104A tumor cells (AG104A–Ld) expressed Ld at a level ∼40-fold above background as measured by flow cytometry (Fig. 1 A). Nevertheless all of the C3H × C57BL/6 F1 mice developed progressively growing lethal, antigen-positive tumors when injected subcutaneously with AG104A–Ld tumor cells. (Fig. 2 A). The tumor also grew progressively in C3H/HeN mice (data not shown). We reasoned that the precursor frequency of Ld-specific T cells in these mice may be too low to match the rapid growth of the Ld-expressing tumor cells. Therefore, AG104A–Ld tumor cells were injected into C3H × 2C anti-Ld TCR transgenic mice (13) in which all CD8+ T cells express the TCR 2C (see Fig. 1 B) that recognizes the Ld antigen in association with a set of closely related natural self-peptides (14, 15). Surprisingly, all of the transgenic mice developed lethal AG104A–Ld tumors despite the predominance of the anti-Ld T cells. In addition, the rate of tumor growth in transgenic mice was unaffected by the presence of the anti-Ld T cells because similar rates of growth were also observed in nontransgenic mice (Fig. 2 A) and nude mice (Fig. 2 B). Reisolation of the AG104A–Ld tumors showed that the expression of the Ld antigen was retained in vivo in the nontransgenic (Fig. 2 C) as well as in the transgenic mice (Fig. 2 D).

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