GM-CSF and B7-1 (CD80) Co-Stimulatory Signals Co-Operate in the Induction of Effective Anti-Tumor Immunity in Syngeneic Mice

Int J Cancer. 1997 Nov 14;73(4):556-61. doi: 10.1002/(sici)1097-0215(19971114)73:4<556::aid-ijc17>3.0.co;2-7.

Abstract

B7-1 (CD80) co-stimulatory molecule gene-transduced Lewis lung carcinoma (LLC) cells (LLC/B7 cells) resulted in remarkable loss of tumorigenicity in syngeneic C57BL/6 mice (87.5% rejection) compared to B7-negative, wild-type LLC (LLC/wt) cells (0% rejection). However, mice that had rejected LLC/B7 cells developed almost no systemic immunity protective against challenge with wild-type tumor cells after 4 weeks (11.8% rejection). Enhancement of MHC class I (H-2Kb) expression of LLC/B7 cells with in vitro interferon-gamma treatment did not result in enhancement of protective immunity. In vivo depletion assay revealed that abrogation of tumorigenicity in LLC/B7 depended on CD8+ T cells but not on CD4+ T cells. However, vaccination of C57BL/6 mice with irradiated LLC cells transduced with GM-CSF (LLC/GM) led to the induction of potent, specific immunity against challenge with the LLC/wt cells after 2 weeks (80.8% rejection). Next, we established a double transfectant of LLC cells expressing both B7-1 and GM-CSF (LLC/GM + B7). The tumorigenicity of these clonal cells was also remarkably suppressed (90% rejection) to the same degree as LLC/B7, whereas that of LLC/GM was not suppressed (0% rejection). Interestingly, mice that had rejected LLC/GM+B7 cells developed enhanced protective immunity against challenge with LLC/wt cells after 4 weeks (55.6% rejection) compared to the results of LLC/B7 cells (11.8%). To evaluate whether co-expression of GM-CSF and B7-1 enabled the tumor cells to activate cytotoxic T cells more efficiently than B7-1 alone, we performed an in vitro killing assay. We found that immunization with LLC/GM+B7 cells resulted in a 3-fold stronger cytotoxic response than that with LLC/B7. Our data indicate that co-transfection of the B7-1 co-stimulatory molecule and GM-CSF genes may be more effective for the induction of stronger protective immunity in this experimental system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism*
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology*
  • B7-1 Antigen / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / immunology
  • Cancer Vaccines / radiation effects
  • Carcinoma, Lewis Lung / immunology*
  • Carcinoma, Lewis Lung / metabolism
  • DNA, Complementary / genetics
  • Female
  • Graft Rejection / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Histocompatibility Antigens Class I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation / immunology
  • Transfection

Substances

  • Antigens, Neoplasm
  • B7-1 Antigen
  • Cancer Vaccines
  • DNA, Complementary
  • Histocompatibility Antigens Class I
  • Granulocyte-Macrophage Colony-Stimulating Factor