Abstract
Macrophages within tumors quell immune attacks on the cancer cells, but a new study shows that tumors also contain a small number of CD103+ dendritic cells that activate antitumor CD8+ T cells. The dendritic cells help shrink tumors in mouse models, and their presence might serve as a prognostic biomarker–and improve the odds of survival for patients.
The tumor microenvironment is often immunosuppressive, but researchers have now discovered that a rare type of dendritic cell avoids inhibition. Boosting the abundance of these cells could provide a new therapy.
Although tumors harbor CD8+ T cells that could destroy them, these cells rarely keep abnormal growth under control. One possible reason is that the T cells aren't sufficiently stimulated by the antigen-presenting cells (APC). CD8+ T cells stop attacking if they aren't regularly re-exposed to target antigens by APCs. Studies have found that myeloid cells—the lineage that includes APCs such as macrophages and dendritic cells—interact with CD8+ T cells inside tumors. However, instead of activating the T cells, the myeloid cells appear to suppress them.
When Matthew Krummel, PhD, of the University of California, San Francisco, and colleagues took a closer look at the tumor-resident myeloid cells, they found that a few dendritic cells behaved differently. In culture, these dendritic cells, which express the distinctive marker CD103, are able to stimulate naïve CD8+ T cells that have never encountered tumor antigens and restimulate previously exposed CD8+ T cells. The CD103+ dendritic cells are sparse, accounting for only about 0.5% of myeloid cells.
The team also found evidence that the novel dendritic cells are beneficial in mice and humans. Infusing mice with tumor-specific T cells slowed tumor growth. However, the effect was smaller if the team eliminated most of the stimulatory dendritic cells from the tumors. Using data from The Cancer Genome Atlas, the researchers found that a gene-expression signature characteristic of CD103+ dendritic cells correlated with a better prognosis in 12 human tumor types, including breast, ovarian, and bladder.
“Within tumors, there are collections of good, antitumor immune cells amid populations we've always thought of as protumor,” says Krummel. He and his colleagues reported their results last month in Cancer Cell.
“Despite [the dendritic cells'] low abundance, there are functional consequences to their presence,” says Niroshana Anandasabapathy, MD, PhD, of Harvard Medical School in Boston, MA, who wasn't connected to the research. The work is “an important bridge to future translational studies,” she says.
Krummel's team now aims to harness CD103+ dendritic cells for therapy. One strategy for boosting antitumor immunity—countering suppressive macrophages—that's already reached clinical trials involves blocking colony-stimulating factor 1, the molecule that spurs differentiation of myeloid cells. However, this approach would also inhibit the CD103+ dendritic cells, Krummel says. He and his colleagues are seeking an alternative that would increase the cells' numbers.
