Limits...
Self antigens expressed by solid tumors Do not efficiently stimulate naive or activated T cells: implications for immunotherapy.

Speiser DE, Miranda R, Zakarian A, Bachmann MF, McKall-Faienza K, Odermatt B, Hanahan D, Zinkernagel RM, Ohashi PS - J. Exp. Med. (1997)

Bottom Line: No significant spontaneous CTL activation against GP was observed.The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo.Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada.

ABSTRACT
Induction and maintenance of cytotoxic T lymphocyte (CTL) activity specific for a primary endogenous tumor was investigated in vivo. The simian virus 40 T antigen (Tag) expressed under the control of the rat insulin promoter (RIP) induced pancreatic beta-cell tumors producing insulin, causing progressive hypoglycemia. As an endogenous tumor antigen, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) was introduced also under the control of the RIP. No significant spontaneous CTL activation against GP was observed. However, LCMV infection induced an antitumor CTL response which efficiently reduced the tumor mass, resulting in temporarily normalized blood glucose levels and prolonged survival of double transgenic RIP(GP x Tag2) mice (137 +/- 18 d) as opposed to control RIP-Tag2 mice (88 +/- 8 d). Surprisingly, the tumor-specific CTL response was not sustained despite the facts that the tumor cells continued to express MHC class I and LCMV-GP-specific CTLs were present and not tolerized. Subsequent adoptive transfer of virus activated spleen cells into RIP(GP x Tag2) mice further prolonged survival (168 +/- 11 d), demonstrating continued expression of the LCMV-GP tumor antigen and MHC class I. The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo. Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy. In addition, the data suggest that the risk for induction of chronic autoimmune diseases is limited, which may encourage immunotherapy against antigens selectively but not exclusively expressed by the tumor.

Show MeSH

Related in: MedlinePlus

Blood glucose levels reflect the tumor burden and the effectiveness of tumor immunotherapy in vivo. (A) RIP(GP × Tag2) and  RIP-Tag2 mice developed hypoglycemia indicative of β-cell hyperplasia  and insulin overproduction, while control RIP-GP and C57BL/6 mice  showed normal glucose levels. (B) Tag2 transgenic animals with two  consecutive blood glucose readings <5 mM (at an age of 70–85 d) and  age-matched control mice were infected with LCMV to induce tumor-specific CTLs. After infection, the GP-expressing mice (but not those  without GP) increased the blood glucose levels. This effect was reversed  in the RIP(GP × Tag2) mice and hypoglycemia relapsed within 4 wk. In  1 out of 10 RIP(GP × Tag2) mice the LCMV-induced hyperglycemia  was very high and lethal. The figures show 1 mouse/group representative  for 7–20 mice/group (4 mice for C57BL/6). ▪, RIP-GP; •, RIP(GP ×  Tag2); ○, RIP-Tag2; □, C57BL/6.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2199023&req=5

Figure 1: Blood glucose levels reflect the tumor burden and the effectiveness of tumor immunotherapy in vivo. (A) RIP(GP × Tag2) and RIP-Tag2 mice developed hypoglycemia indicative of β-cell hyperplasia and insulin overproduction, while control RIP-GP and C57BL/6 mice showed normal glucose levels. (B) Tag2 transgenic animals with two consecutive blood glucose readings <5 mM (at an age of 70–85 d) and age-matched control mice were infected with LCMV to induce tumor-specific CTLs. After infection, the GP-expressing mice (but not those without GP) increased the blood glucose levels. This effect was reversed in the RIP(GP × Tag2) mice and hypoglycemia relapsed within 4 wk. In 1 out of 10 RIP(GP × Tag2) mice the LCMV-induced hyperglycemia was very high and lethal. The figures show 1 mouse/group representative for 7–20 mice/group (4 mice for C57BL/6). ▪, RIP-GP; •, RIP(GP × Tag2); ○, RIP-Tag2; □, C57BL/6.

Mentions: To generate double transgenic RIP(GP × Tag2) mice, tumor-susceptible RIP-Tag2 mice were crossed with transgenic RIP-GP mice expressing the LCMV-GP on pancreatic β cells. To monitor tumor progression, blood glucose was measured regularly. Pathological hypoglycemia (i.e., multiple values <5 mM glucose) corresponded with a large tumor burden since the β-islet tumor cells autonomously released high quantities of insulin (22). This occurred in tumor-bearing RIP-Tag2 and RIP(GP × Tag2) mice, which both developed hypoglycemia at the age of 70–85 d (Fig. 1 A). As expected, control C57BL/6 and RIP-GP mice showed normal blood glucose levels. The RIP(GP × Tag2) mice developed tumors and hypoglycemia with identical kinetics to RIP-Tag2 mice suggesting that the LCMV-GP specific T cells did not spontaneously develop tumor protective activity.


Self antigens expressed by solid tumors Do not efficiently stimulate naive or activated T cells: implications for immunotherapy.

Speiser DE, Miranda R, Zakarian A, Bachmann MF, McKall-Faienza K, Odermatt B, Hanahan D, Zinkernagel RM, Ohashi PS - J. Exp. Med. (1997)

Blood glucose levels reflect the tumor burden and the effectiveness of tumor immunotherapy in vivo. (A) RIP(GP × Tag2) and  RIP-Tag2 mice developed hypoglycemia indicative of β-cell hyperplasia  and insulin overproduction, while control RIP-GP and C57BL/6 mice  showed normal glucose levels. (B) Tag2 transgenic animals with two  consecutive blood glucose readings <5 mM (at an age of 70–85 d) and  age-matched control mice were infected with LCMV to induce tumor-specific CTLs. After infection, the GP-expressing mice (but not those  without GP) increased the blood glucose levels. This effect was reversed  in the RIP(GP × Tag2) mice and hypoglycemia relapsed within 4 wk. In  1 out of 10 RIP(GP × Tag2) mice the LCMV-induced hyperglycemia  was very high and lethal. The figures show 1 mouse/group representative  for 7–20 mice/group (4 mice for C57BL/6). ▪, RIP-GP; •, RIP(GP ×  Tag2); ○, RIP-Tag2; □, C57BL/6.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199023&req=5

Figure 1: Blood glucose levels reflect the tumor burden and the effectiveness of tumor immunotherapy in vivo. (A) RIP(GP × Tag2) and RIP-Tag2 mice developed hypoglycemia indicative of β-cell hyperplasia and insulin overproduction, while control RIP-GP and C57BL/6 mice showed normal glucose levels. (B) Tag2 transgenic animals with two consecutive blood glucose readings <5 mM (at an age of 70–85 d) and age-matched control mice were infected with LCMV to induce tumor-specific CTLs. After infection, the GP-expressing mice (but not those without GP) increased the blood glucose levels. This effect was reversed in the RIP(GP × Tag2) mice and hypoglycemia relapsed within 4 wk. In 1 out of 10 RIP(GP × Tag2) mice the LCMV-induced hyperglycemia was very high and lethal. The figures show 1 mouse/group representative for 7–20 mice/group (4 mice for C57BL/6). ▪, RIP-GP; •, RIP(GP × Tag2); ○, RIP-Tag2; □, C57BL/6.
Mentions: To generate double transgenic RIP(GP × Tag2) mice, tumor-susceptible RIP-Tag2 mice were crossed with transgenic RIP-GP mice expressing the LCMV-GP on pancreatic β cells. To monitor tumor progression, blood glucose was measured regularly. Pathological hypoglycemia (i.e., multiple values <5 mM glucose) corresponded with a large tumor burden since the β-islet tumor cells autonomously released high quantities of insulin (22). This occurred in tumor-bearing RIP-Tag2 and RIP(GP × Tag2) mice, which both developed hypoglycemia at the age of 70–85 d (Fig. 1 A). As expected, control C57BL/6 and RIP-GP mice showed normal blood glucose levels. The RIP(GP × Tag2) mice developed tumors and hypoglycemia with identical kinetics to RIP-Tag2 mice suggesting that the LCMV-GP specific T cells did not spontaneously develop tumor protective activity.

Bottom Line: No significant spontaneous CTL activation against GP was observed.The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo.Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Ontario Cancer Institute, Department of Medical Biophysics and Department of Immunology, University of Toronto, Ontario M5G 2M9, Canada.

ABSTRACT
Induction and maintenance of cytotoxic T lymphocyte (CTL) activity specific for a primary endogenous tumor was investigated in vivo. The simian virus 40 T antigen (Tag) expressed under the control of the rat insulin promoter (RIP) induced pancreatic beta-cell tumors producing insulin, causing progressive hypoglycemia. As an endogenous tumor antigen, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) was introduced also under the control of the RIP. No significant spontaneous CTL activation against GP was observed. However, LCMV infection induced an antitumor CTL response which efficiently reduced the tumor mass, resulting in temporarily normalized blood glucose levels and prolonged survival of double transgenic RIP(GP x Tag2) mice (137 +/- 18 d) as opposed to control RIP-Tag2 mice (88 +/- 8 d). Surprisingly, the tumor-specific CTL response was not sustained despite the facts that the tumor cells continued to express MHC class I and LCMV-GP-specific CTLs were present and not tolerized. Subsequent adoptive transfer of virus activated spleen cells into RIP(GP x Tag2) mice further prolonged survival (168 +/- 11 d), demonstrating continued expression of the LCMV-GP tumor antigen and MHC class I. The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo. Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy. In addition, the data suggest that the risk for induction of chronic autoimmune diseases is limited, which may encourage immunotherapy against antigens selectively but not exclusively expressed by the tumor.

Show MeSH
Related in: MedlinePlus