CD40L-Expressing Dendritic Cells Eliminate Breast Tumors in Mice

ORLANDO—Intratumoral injection of dendritic cells genetically modified to express CD40 ligand (CD40L) eradicated breast tumors in mice, Zoya R. Yurkovetsky, a PhD student from the Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, reported at the Era of Hope Department of Defense Breast Cancer Research Program meeting.

Naïve T cells require help from antigen-presenting cells, the most powerful being the dendritic cells, Ms. Yurkovetsky said. Dendritic cells are generated in the bone marrow and travel through the bloodstream to different tissue, including tumors. Dendritic cells are controlled by different cytokines.

The researchers focused on the CD40 receptor and the protein CD40L, which plays an active role in dendritic cell generation, migration, functioning, survival, and critical regulation in the lymph node. Tumors depress CD40L expression.

The researchers injected dendritic cells engineered to express CD40L (DC/CD40L) directly into TS/A breast tumors in six mice. Control mice were given saline injections. "We saw a complete rejection of tumor growth in five out of six mice given DC/CD40L, and in the sixth, the tumor was reduced to a small size," Ms. Yurkovetsky said. The tumor steadily progressed in the control animals. "CD40 ligand increased the cytotoxic effect of T cells," she said.

When the researchers rechallenged the treatment group with the same TS/A tumor, the tumor cells did not proliferate, an indication of immune memory. "This effect, with generation of specific immune memory, protects the animal from tumor growth," she said.

The team found that CD40L caused the dendritic cells to produce additional interleukin-12, an immunostimulatory cytokine previously associated with antitumor activity.

The researchers also noted that more dendritic cells infiltrated the tumors in the treatment group than in the control group. "A high concentration of dendritic cells at the tumor is associated with better prognosis and decreased metastasis," Ms. Yurkovetsky said.

The researchers are still working to learn more about where the dendritic cells travel after they are injected; where they stimulate the T cells, at the tumor site or in the lymph nodes; and what the mechanism may be.

In similar studies with colon cancer, DC/CD40L injection reduced tumor size but did not eliminate the malignancies. Ms. Yurkovetsky said that the team plans to investigate response in other tumor types.

"To summarize our data, we have shown that tumor inhibits CD40 expression on dendritic cells and their functional activities," she said. "We also showed that dendritic cells overexpress-ing CD40 ligand demonstrate a strong antitumor effect with generation of specific immune memory."