MIT researchers discover possible new ways to fight tumors

Under the right circumstances, the body T cells It can detect and destroy cancer cells. However, in most cancer patients, T cells are disarmed when they enter the environment surrounding the tumor.

Scientists are now trying to find ways to help treat patients by jump-starting these matte T cells. Much of the research in this area, known as cancer immunotherapy, focuses on finding ways to directly stimulate these T cells. Researchers at MIT have discovered new ways to indirectly activate these T cells by mobilizing a population of helper immune cells called dendritic cells.

In a new study, researchers identified a specific subset of dendritic cells that had their own way of activating T cells. These dendritic cells can hide in tumor proteins and impersonate cancer cells to provoke a strong T-cell response.

We knew that dendritic cells were very important for the antitumor immune response, but we did not know what really constitutes the optimal dendritic cell response to the tumor. “

Stefani Spranger, Howard S., Linda B. Stern, Professor of Career Development, Member of MIT’s Koch Institute for Integrative Cancer Research

The results suggest that finding a way to stimulate a particular population of dendritic cells may help increase the effectiveness of cancer immunotherapy, she says. In mouse studies, researchers stimulated these dendritic cells, melanoma And colon tumors.

Spranger is the lead author of this study and is published in the journal today. Immunity.. The lead author of this paper is Ellen Duong, a graduate student at MIT.

Natural regression

When a tumor begins to form, it produces a cancerous protein that T cells recognize as a foreign body. This may allow the tumor to be eliminated before the T cells become very large. In other cases, the tumor can secrete chemical signals that inactivate T cells, allowing the tumor to continue to grow unsuppressed.

Dendritic cells are known to help activate T cells that fight tumors, but there are many different subtypes of dendritic cells, and their individual role in T cell activation is complete. Not characterized. In this study, the MIT team wanted to investigate what types of dendritic cells were involved in the T cell response to successfully eliminate tumors.

To do so, they discovered a tumor cell line from certain muscle tumors that has been shown to spontaneously regress in mice. Such cell lines are difficult to find, as researchers usually do not maintain them if they are unable to form tumors, says Spranger.

They studied mice and compared the tumors produced by their degenerative cell lines to the types of colon cancer that form tumors that grow after being transplanted into the body. Researchers have found that T cell responses are quickly exhausted in ongoing tumors and that T cells continue to function in regressive tumors.

Next, the researchers analyzed the dendritic cell populations present in each of these tumors. One of the main functions of dendritic cells is to take up debris from dying cells, such as cancer cells and cells infected with pathogens, and present protein fragments to T cells to warn of infections and tumors.

The most well-known type of dendritic cell required for anti-tumor immunity is DC1 cell, which interacts with T cells that can eliminate cancer cells. However, researchers have found that DC1 cells are not required for tumor regression. Instead, a previously unknown activation state of DC2 cells, a different type of dendritic cell that promotes T cell activation in regressing tumors using single-cell RNA sequencing technology. Has been identified.

Instead of ingesting cell debris, the MIT team discovered that these dendritic cells swipe a protein called the MHC complex from tumor cells and display them on their own surface. When T cells encounter these dendritic cells disguised as tumor cells, they are strongly activated and begin to kill the tumor cells.

This special population of dendritic cells appears to be activated by type 1 interferon, a signaling molecule normally produced by cells in response to viral infections. Researchers have found small populations of these dendritic cells in advanced colon and melanoma tumors, but they have not been properly activated. However, when those tumors were treated with interferon, the dendritic cells began to stimulate T cells to attack the tumor cells.

Target therapy

Although some types of interferon have been used to help treat cancer, systemic administration can cause widespread side effects. The results of this study suggest that it may be beneficial to deliver interferon to tumor cells in a very targeted manner, or to use drugs that induce tumor cells to produce type I interferon. Suggests.

Researchers are currently planning to investigate how much type I interferon is needed to generate a strong T cell response. Most tumor cells produce small amounts of type I interferon, but not enough to activate the dendritic cell population that activates T cells. On the other hand, too much interferon can cause cell toxicity.

“Our immune system is wired to react very dramatically to the subtle differences in type I interferon, which is interesting from an immunological point of view,” says Spranger.

This study was funded by the Koch Institute Support (Core) Grant from the National Cancer Institute, the National Health Institute Pre-Phase Training Grant, the David H. Koch Graduate Fellowship, and the Pew Steward Fellowship. ..