Cancer dormancy. VII. A regulatory role for CD8(+) T cells and IFN-gamma in establishing and maintaining the tumor-dormant state

Dormant turner cells resistant to ablative cancer therapy represent a signi ficant clinical obstacle due to later relapse. Experimentally, the murine B cell lymphoma (BCL1) is used as a model of tumor dormancy in mice vaccinat ed with the BCL1 Ig. Here, we used this model to explore the cellular mecha nisms underlying dormancy. Our previous studies have demonstrated that T ce ll-mediated immunity is an important component in the regulation of tumor d ormancy because Id-immune T cells adoptively transferred into passively imm unized SCID mice challenged with BCL1 cells significantly increased the inc idence and duration of the dormant state. We have extended these observatio ns and demonstrate that CD8(+), but not CD4(+), T cells are required for th e maintenance of dormancy in BCL1 Ig-immunized BALB/c mice, In parallel stu dies, the transfer of Id-immune CD8(+) cells, but not Id-immune CD4(+) cell s, conferred significant protection to SCID mice passively immunized with n onprotective levels of polyclonal anti-Id and then challenged with BCL1 cel ls. Furthermore, the ability of CD8(+) T cells to induce a state of dormanc y in passively immunized SCID mice was completely abrogated by treatment wi th neutralizing alpha-IFN-gamma mAbs in vivo. In vitro studies demonstrated that IFN-gamma alone or in combination with reagents to; cross-link the su rface Ig induced both cell cycle arrest and apoptosis in a BCL1 cell line. Collectively, these data demonstrate a role for CDS' T cells via endogenous production of IFN-gamma in collaboration,vith humoral immunity to both ind uce and maintain a state of tumor dormancy.