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

H Koehler, D Kofler, A Hombach, H Abken - Cancer research, 2007 - AACR
H Koehler, D Kofler, A Hombach, H Abken
Cancer research, 2007AACR
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-β (TGF-β). 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 …
Abstract
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-β (TGF-β). 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 CD3ζ on binding to CEA. Immunoreceptor-activated T cells secrete IFN-γ, proliferate, and lyse CEA+ but not CEA tumor cells. Whereas IL-10 has no direct effect on immunoreceptor-triggered effector functions, TGF-β represses proliferation of both CD4+ and CD8+ T cells but neither IFN-γ secretion nor specific cytolytic activities. CD28 costimulation, however, overcomes TGF-β–mediated repression in T-cell proliferation. Consequently, T cells redirected by a combined CD28-CD3ζ signaling immunoreceptor are largely resistant to TGF-β–mediated repression. This is reflected in vivo by a more pronounced antitumor activity of T cells against TGF-β–secreting tumors when redirected by a costimulatory CD28-CD3ζ than by a CD3ζ signaling immunoreceptor. [Cancer Res 2007;67(5):2265–73]
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