Activation of tolerogenic dendritic cells in the tumor draining lymph nodes by CD8+ T cells engineered to express CD40 ligand.
Tolerogenic dendritic cells in the tumor microenvironment can inhibit the generation and maintenance of robust antitumor T cell responses. In this study, we investigated the effects of local delivery of CD40L by tumor-reactive CD8(+) T cells on dendritic cell activation and antitumor T cell responses in the TRAMP model. To increase the immunostimulatory signal, CD40L was engineered, by deleting the majority of the cytoplasmic domain, to increase its levels of expression and duration on the surface of CD8(+) T cells. Tumor-reactive CD8(+) T cells expressing the truncated form of CD40L stimulated maturation of dendritic cells in vitro and in the prostate draining lymph nodes in vivo. Following dendritic cell maturation, a significantly higher fraction of adoptively transferred, tumor-reactive (reporter) CD8(+) T cells was stimulated to express IFN-gamma and infiltrate the prostate tissue. The antitumor CD8(+) T cell response was further enhanced if TRAMP mice were also immunized with a tumor-specific Ag. These findings demonstrate that augmented T cell responses can be achieved by engineering tumor-reactive T cells to deliver stimulatory signals to dendritic cells in the tumor microenvironment.
Higham
Eileen M
EM
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Wittrup
K Dane
KD
Chen
Jianzhu
J
D019264:Adoptive Transfer; D000818:Animals; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*
D019496:Cancer Vaccines; D023201:CD40 Ligand