Cutting edge: delay and reversal of T cell tolerance by intratumoral injection of antigen-loaded dendritic cells in an autochthonous tumor model.
The tumor environment exerts a powerful suppressive influence on infiltrating tumor-reactive T cells. It induces tolerance of adoptively transferred effector T cells as they enter tumors and maintains the tolerance of persisting tumor-infiltrating T cells. In an autochthonous prostate cancer model, in which tumor-reactive CD8 T cells are trackable, we demonstrate that both depletion of endogenous dendritic cells (DCs) and intratumoral injection of Ag-loaded mature DCs delayed the tolerization of tumor-infiltrating effector CD8 T cells. Intratumoral injection of Ag-loaded DCs also reactivated tolerized CD8 T cells in the tumor tissue. The observed effects lasted as long as the injected DCs persisted. These findings are consistent with a critical role of DCs in modulating T cell reactivity in the tumor environment. They also suggest new potential strategies to extend the functionality of transferred effector T cells and to restore function to tolerized tumor-infiltrating T cells for cancer immunotherapy.
Higham
Eileen M
EM
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Shen
Ching-Hung
CH
Wittrup
K Dane
KD
Chen
Jianzhu
J
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology*