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CD28 Costimulation Overcomes Transforming Growth Factor-ß–Mediated Repression of Proliferation of Redirected Human CD4⁺ and CD8⁺ T Cells in an Antitumor Cell Attack

Tumorgenetik, Klinik I für Innere Medizin and Zentrum für Molekulare Medizin Köln, Universität zu Köln, Köln, Germany

Requests for reprints: Hinrich Abken, Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Kerpener Str. 62, D-50924 Köln, Germany. Phone: 49-221-478-4130; Fax: 49-221-478-7414; E-mail: hinrich.abken{at}uk-koeln.de.

The T-cell–mediated antitumor immune response is frequently repressed in the tumor environment by an immunologic barrier, the predominant mediators of which are thought to be interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß). We explored the effect of these cytokines on the individual T-cell effector functions on antigen engagement during an antitumor cell attack. Isolated CD4⁺ and CD8⁺ T cells were antigen-specifically redirected toward carcinoembryonic antigen (CEA)-positive tumor cells by expression of a recombinant T-cell receptor (immunoreceptor), which triggers T-cell activation via CD3 on binding to CEA. Immunoreceptor-activated T cells secrete IFN-, proliferate, and lyse CEA⁺ but not CEA^– tumor cells. Whereas IL-10 has no direct effect on immunoreceptor-triggered effector functions, TGF-ß represses proliferation of both CD4⁺ and CD8⁺ T cells but neither IFN- secretion nor specific cytolytic activities. CD28 costimulation, however, overcomes TGF-ß–mediated repression in T-cell proliferation. Consequently, T cells redirected by a combined CD28-CD3 signaling immunoreceptor are largely resistant to TGF-ß–mediated repression. This is reflected in vivo by a more pronounced antitumor activity of T cells against TGF-ß–secreting tumors when redirected by a costimulatory CD28-CD3 than by a CD3 signaling immunoreceptor. [Cancer Res 2007;67(5):2265–73]