Dana-Farber Research Awakens Dendritic Cells Against Cancer

Imagine reporting for duty and finding your director asleep, or worse, absent. Without a place to go and a task to perform, you have little choice but to sit idle.

This scenario is exactly what cancer wants for T cells, the foot soldiers of the immune system. T cells get their marching orders to fight tumors from immune cells called dendritic cells. But tumors can create protective environments that keep dendritic cells dozing and unable to mobilize anti-tumor forces.

New research from the lab of Kai Wucherpfennig, MD, PhD, has found a way to reawaken dendritic cells and get them to rally T cells to fight cancer. The team found that an enzyme called CARM1 tunes the activity of dendritic cells, ensuring they are active when the body needs an immune response and quiet when it does not. Inhibiting CARM1 at the site of a cancer vaccine injection in mice dramatically improved the activity of the vaccine, suggesting that CARM1 could be a promising anticancer target.

“CARM1 is the first target for enhancing dendritic cells in tumors,” says Wucherpfennig, who published the study in Science. “Many people study T cells, but you cannot just study T cells in isolation. You have to ask what else needs to happen for the T cells to work effectively, and there’s mounting evidence showing that dendritic cells are essential for T cells to fight cancer.”

A system view

Dendritic cells are produced in the bone marrow. They travel throughout the body and scan for trouble. If they encounter tumor cells, they pick up fragments of these cells, called antigens, that can be used to find more cancer cells later.

Dendritic cells then travel to the nearest lymph node, where T cells await their instructions. The dendritic cells pass along the antigens they’ve found and send the T cells off on a hunt for cancer cells to destroy. Tumors, however, secrete factors that dampen the function of dendritic cells, which in turn reduces the activity of T cells.

Wucherpfennig has been studying this system of dendritic cells and T cells to look for novel ways to tune them to be more active against cancer, even when cancer has cast them under its sleeping spell.

“We are trying to find novel strategies where you have a cooperative response, where all of the components are working together against the cancer,” says Wucherpfennig.

Homing in on CARM1

Wucherpfennig’s lab initially learned about CARM1 by studying its role in T cells and tumor cells. The first discoveries, made a few years ago, found that dialing down levels of CARM1 in T cells and tumor cells enhanced the activity of T cells against cancer and slowed tumor growth.

In this study, the team eliminated CARM1 in dendritic cells alone. This alteration enhanced the activity and abundance of these cells in tumors and improved their ability to find and present antigens to T cells.

Together, the findings show that CARM1 acts as a sensor. Signals in the tumor microenvironment trigger CARM1 to make the system more active or quiet by regulating key genetic programs related to antitumor immunity.

“The system is very precisely tuned to not stimulate an immune response when one is not necessary, and this is what cancer takes advantage of,” says Wucherpfennig.

Wucherpfennig followed these findings with a test of a cancer treatment strategy focused on tuning CARM1 in dendritic cells specifically. He delivered a CARM1 inhibitor with a cancer vaccine under the skin in mice so it would only affect dendritic cells in nearby lymph nodes and not directly affect other cells, including cancer cells or T cells.

The results showed that dendritic cell activity increased substantially in tumors, as did activity of T cells that were primed by the vaccine to fight cancer. In addition, mice treated with the combination had a survival advantage.

“Dendritic cells are a limiting factor in the efficacy of cancer vaccines, so this could be an effective strategy to improve their benefits to patients,” says Wucherpfennig.

The human connection

This strategy has so far been tested only in mice, but Wucherpfennig’s study showed that CARM1’s role in tuning dendritic cells carries over to humans. Using dendritic cells induced from human bone marrow stem cells, the team found that CARM1 dials dendritic cell function up and down exactly as expected.

The CARM1 inhibitor Wucherpfennig’s team is using, however, is not suited for clinical use in humans. So Wucherpfennig has partnered with Dana-Farber chemist Lyn Jones, PhD, to develop a next-generation CARM1 inhibitor. The work is funded by the Dana-Farber Accelerator, in the Belfer Office of Dana-Farber Innovations, which aims to shorten the time it takes for important research findings to benefit patients, and by the Melanoma Research Foundation and the Parker Institute for Cancer Immunotherapy.

He is also developing a strategy for selecting the forms of cancer most likely those considered to be “cold,” meaning they have little dendritic cell or T cell activity inside of them – to focus on in clinical trials.