B7-2 expression above a threshold elicits anti-tumor immunity as effective as interleukin-12 and prolongs survival in murine B-cell lymphoma.
The costimulatory molecule, B7-2, is expressed by various lymphomas, but this level of expression is not sufficient to generate effective anti-tumor immunity in vivo. To determine whether up-regulated expression of the costimulatory molecule, B7-2, leads to more effective anti-tumor immunity in vivo, the A20 murine model of B-cell lymphoma was used. A20 tumor cells express major histocompatibility complex (MHC) I and II molecules and moderate constitutive levels of B7-2. While B7-1 and B7-2 have been introduced into tumor cells lacking these molecules, studies have not been conducted to determine whether tumors that constitutively express B7-1 or B7-2 can be made more immunogenic by increasing the expression of these molecules. In this report, A20/B7-2 transfectants expressing greater levels of B7-2 were rejected in syngeneic mice, and systemic immunity against the A20 parental cells was generated. Treatment with the A20/B7-2 variant cells significantly improved the survival of tumor-bearing mice. Coinjection with IL-12 secreting variants did not further augment the anti-tumor immunity observed for B7-2 therapy alone. Both CD8(+) T cells and natural killer (NK) cells mediated the anti-tumor immune response observed in A20/B7-2 immunized mice. In mice that developed tumors after immunization with the A20/B7-2 variant cells, resected tumor cells were shown to express lower levels of B7-2 than the transfected variants. These results suggest that the level of costimulation is important for the generation of anti-tumor immunity and for host survival. In addition, tumors appear to be able to evade the immune response by downregulating the expression of B7-2 below a threshold level.
Pizzoferrato
Eva
E
Department of Surgery, Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. pizzoferatoe@msx.upmc.edu
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D051940:B7-2 Antigen; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D018664:Interleukin-12 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000401:mortality; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015996:Survival Rate
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D018664:Interleukin-12