Activation of tumor-specific CD8+ T Cells after intratumoral Ad5-TRAIL/CpG oligodeoxynucleotide combination therapy.
CD8(+) T-cell activation via cross-presentation of antigens from apoptotic tumor cells is controversial. Dendritic cells capture naturally shed tumor antigens and cross-present them to CD8(+) T cells; unfortunately, the frequency of activated CD8(+) T cells is often too low to mount an effective response against the tumor. By increasing the amount of antigen for presentation, a larger T-cell response can be theoretically elicited. We used a recombinant adenovirus encoding full-length murine tumor necrosis factor-related apoptosis-inducing ligand (Ad5-mTRAIL) to induce tumor cell apoptosis, and when given intratumorally to mice bearing experimental renal cell carcinoma (Renca) tumors, Ad5-mTRAIL minimally prolonged survival and induced a low level of CTL activity. To enhance dendritic cell efficiency, an immunostimulatory CpG oligodeoxynucleotide (CpG ODN) was combined with Ad5-mTRAIL. This combination therapy significantly augmented in vivo antigen-specific T-cell proliferation and CTL activity, as well as prolonged survival of Renca tumor-bearing mice. Interestingly, depletion of CD4(+) or CD25(+) cells before therapy further enhanced survival and in vivo CTL activity. In addition, tumor-free mice depleted of CD4(+) cells were also able to reject a subsequent challenge of Renca cells, but not MHC-matched RM-11 prostate tumor cells, demonstrating the existence of immunologic memory. These results collectively show that local treatment with Ad5-mTRAIL and CpG ODN can augment tumor antigen cross-presentation resulting in T-cell proliferation, enhanced CTL activity, and increased animal survival.
VanOosten
Rebecca L
RL
Department of Urology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa 52242-1089, USA.
Griffith
Thomas S
TS
D000230:Adenocarcinoma / Q000276:immunology*; D000256:Adenoviridae; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D007680:Kidney Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D010587:Phagocytosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D053221:TNF-Related Apoptosis-Inducing Ligand; D001613:beta 2-Microglobulin