Many cancer patients may need one stroke of two sequential immunotherapies


Anti-PD-1 cancer immunotherapy increases T cells that fight cancer in the body, but in many patients Tfr suppressor cells slow this progress. Credit: La Jolla Institute for Immunology

New research led by scientists at the La Jolla Institute of Immunology (LJI) and the University of Liverpool may explain why many cancer patients do not respond to anti-PD-1 cancer immunotherapies, also called inhibitors. from the control point.

The team reports that these patients may have tumors with a high number of T-follicle (Tfr) regulatory cells.

In a healthy person, Tfr cells do the important task of stopping wire T cells and autoantibodies to attack the body’s own tissues. But in one , Tfr cells drastically mark the body’s ability to kill .

Anti-PD-1 immunotherapies increase T cells that fight cancer in the body, but in many patients Tfr suppressor cells slow this progress.

With this new understanding of what is happening within tumors, researchers believe that first treating these patients with drugs to deplete Tfr cells can encourage the body to respond to subsequent anti-PD-1 therapies and increase overall survival.

“Our data is beginning to point the way to how we could improve cancer treatments,” says study co-leader Christian H. Ottensmeier, MD, Ph.D., FRCP, professor at the University of Liverpool and adjunct professor at LJI.

The study was published on June 24, 2021 in the journal Immunology of nature.

Why Tfr cells are important

Anti-PD-1 cancer immunotherapies work by increasing the body’s ability to produce more cancer-targeted T cells. LJI professor Pandurangan Vijayanand, MD, Ph.D., who acted as a senior co-author of the new study, compares anti-PD-1 therapies with putting one foot on the body accelerator. .

Unfortunately, not all patients respond to these immunotherapies, and scientists have found that anti-PD-1 treatment can lead to worse outcomes in a small group of people. The new study suggests that Tfr cells may be to blame when anti-PD-1 therapies fail in some patients.

Scientists only described Tfr cells about ten years ago. At this time, the researchers found that these cells help control the strength of the body’s B cell responses. Nothing was known about its role in cancers.

For the new study, researchers examined samples from human tumors from six different types of cancer: liver cancer, melanoma, colorectal cancer, non-small cell lung cancer, head and neck cancer, and breast cancer. The team used monocellular RNA sequencing technology to detect the presence of Tfr cells in these tumors.

The researchers found that tumors resistant to anti-PD-1 therapies also have a large number of Tfr cells. “Tfr cells are much more suppressive than normal T-regulatory cells and stick for longer in tumor tissues,” says LJI instructor Simon Eschweiler, Ph.D., who was the first author of the study.

To make matters worse, Tfr cells are actually activated by anti-PD-1 therapies.

“When you have many of these suppressor cells, anti-PD-1 it can be harmful, “says Vijayanand. The immune system does not get the boost it is supposed to receive from treatment.” The brake is on, you’re not going anywhere. “

Luckily, scientists have the tools to counteract Tfr cells. Cancer immunotherapies called anti-CTLA-4 treatments can deplete the body’s Tfr reserve. New research suggests that patients with high Tfr numbers may benefit from sequential treatments, where doctors begin anti-CTLA-4 therapy and then move on to anti-PD-1 therapy. However, this approach needs to be validated in clinical trials.

Bring this discovery to the clinic

A more detailed look at melanoma cases added more evidence that selective and sequential immunotherapy treatments may be the best way to help patients with higher Tfr cell numbers in their tumors.

In a retrospective study of 271 patients with melanoma, the researchers found that treatment of patients with anti-CTLA-4 therapy, followed by anti-PD-1, was associated with a significant increase in their overall survival. patients, compared with the treatment of patients with anti-PD -1 or anti-CTLA-4, or using both treatments simultaneously.

Ottensmeier explains that this type of retrospective study may be skewed because of the history of patients and the drugs available at the time, but the findings are an important sign that researchers are on the right track toward a better way to help patients. patients.

The researchers then plan to establish a randomized clinical trial where they can deplete Tfr cells in cancer patients before doing PD-1 therapy. Researchers warn that depopulation of these cells can cause side effects if other types of regulatory T cells are also depleted.

“If you take these cells everywhere, you could eliminate the immune block that is really necessary for our well-being,” Ottensmeier says.

“We are thinking of other ways to deplete this population, outside of anti-CTLA-4 therapies, and we are collaborating with Cancer Research UK to develop therapies targeted at these cell types,” says Vijayanand.

Researchers are also working on developing a biomarker that can function as a test to tell doctors how many of these Tfr they are present in a given tumor.

Orientation against estrogen-resistant breast cancer

More information:
Intratumor follicular regulatory T cells reduce the effectiveness of anti-PD-1 treatment, Immunology of nature (2021). DOI: 10.1038 / s41590-021-00958-6 ,

Citation: Many cancer patients may need a two-course sequential immunotherapy (2021, June 24) retrieved June 24, 2021 at one-two-immunotherapies .html

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