International Immunology, Vol 9, 1259-1269, Copyright © 1997 by Oxford University Press
F Fallarino, A Ashikari, T Boon and TF Gajewski
Transfection of modestly immunogenic tumors to express B7 family co-
stimulator molecules results in their rejection by syngeneic mice,
suggesting a possible clinical application in cancer patients. Immunization
of naive mice with irradiated B7-1-transfected P1.HTR cells is sufficient
to induce specific cytolytic T lymphocytes (CTL) and to protect against
tumor challenge. However, patients to be treated will have an existing
tumor burden; thus, preclinical models should examine therapeutic efficacy
in an established tumor setting. Contrary to expectations, immunization of
mice with irradiated B7-1-transfected P1.HTR cells had no impact on the
growth of pre-established control- transfected tumors. Mice bearing
control-transfected P1.HTR tumors successfully rejected living B7-1
transfectants on the contralateral flank, demonstrating the ability of
tumor-bearing mice to respond to B7 co-stimulation. Inasmuch as IL-12 is
another important factor for CTL maturation, P1.HTR transfectants
expressing B7-1 and/or IL-12 were then constructed. Remarkably, regression
of pre-established tumors was achieved following immunization with
irradiated IL-12 transfectants, even without co-expression of B7-1.
Rejection required a shared antigen with the tumor used for immunization,
could not be reproduced with rIL- 12 alone, depended on host T lymphocytes
and correlated with a high IFN- gamma-producing T cell phenotype. In
addition, IL-12-facilitated tumor rejection required co-operation with a
CTLA-4 ligand provided by the host, and correlated with up-regulation of
B7-1 and B7-2 on host antigen-presenting cells. Thus, active immunization
in the established tumor setting is benefitted greatly by the provision of
IL-12, which may recruit participation of sufficient B7 co-stimulation from
the host that it need not be provided exogenously.
ARTICLES
Antigen-specific regression of established tumors induced by active immunization with irradiated IL-12- but not B7-1-transfected tumor cells
Department of Medicine, University of Chicago Medical Center, IL 60637, USA.
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