Role Of Cd8(+) T Cell Activation Status In Determining Susceptibility To Tumor-Induced Immune Suppression

Adoptive transfer of tumor-reactive T cells represents a potentially powerful tool in the therapy of cancer. However, clinical outcomes continue to be disappointing for unknown reasons. Here, using the B16 murine melanoma model, we show that effector CD8+ T cells, such as those generated in vitro in adoptive therapy protocols, are significantly more susceptible to tumor-induced immune suppression than naïve T cells of the same clonotype. In contrast, in vivo-generated memory T cells are resistant to suppression. Depletion of CD4+ T cells or neutralization of the signaling protein transforming growth factor β (TGFβ) potently reduces levels of immune suppression. Furthermore, TGFβ receptor II (TGFβRII) is upregulated on the surface of effector T cells relative to naïve T cells, suggesting that sensitivity to TGFβ may cause the differential susceptibility to immune suppression. Our findings support a role for T cell activation status in susceptibility to tumor-induced immune suppression and suggest that interference with TGFβ signaling in adoptively transferred effector cells or conferring memory-like resistance to suppression may improve clinical responses to adoptive therapy. Supported by the Illinois Division of the American Cancer Society (J.A.G.) and the Cancer Research Foundation (J.A.G.).