T-cells Need Extra Boost After Activation by Immune Checkpoint Inhibitors, Study Shows

T-cells Need Extra Boost After Activation by Immune Checkpoint Inhibitors, Study Shows

Drugs used to treat some cancers still may need an extra boost to be effective, and a recent study found that stimulating the CD28 receptor might be the answer.

Researchers found that certain lung cancer patients were lacking CD28 at the surface of their body’s own cancer-fighting cells. Blocking CD28 in mice kept their killer cells from multiplying.

The study, “Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent,” was published by researchers at the Emory Vaccine Center and physicians at the Winship Cancer Institute in the journal Science.

The blood cells in the body that fight cancer are known as CD8 T-cells, a special kind of white blood cell that recognize specific targets to attack, such as tumor cells. But tumor cells can block these T-cells, and FDA-approved drugs called checkpoint inhibitors are able to unblock the T-cells, allowing them to multiply and kill tumor cells.

These checkpoint inhibitors, like PD-1-blocking drugs, act by blocking a naturally occurring substance, the PD-1 protein, on the surface of the T-cells, but they are not always successful in treating cancer patients. This study set out to find out why.

It turns out that another protein on the surface of the T-cells, called CD28, may also be needed to completely unblock the T-cells.

When the CD28 protein was blocked or eliminated in mice, the T-cells did not multiply as they should have when the mice were treated with PD-1 blocking drugs. While PD-1 has to be blocked, CD28 may also have to be activated so that the T-cells can do their work.

The study found that the percentage of T-cells with CD28 on their surface in the lungs of patients with early stage lung cancer varied, ranging from 20 to 90 percent. This might make it possible to predict which lung cancer patients will be successfully treated with PD-1 blocking drugs. It may also be possible to develop drugs that stimulate CD28 for use in combination with PD-1-blocking drugs.

“We observed that in tumors from lung cancer patients, many of the infiltrating PD-1+ CD8 T-cells do not express CD28, and thus according to our data from experiments in mice, those CD28-negative cells may not proliferate when the PD-1 pathway is blocked,” lead author Alice Kamphorst, PhD, said in a news release.

“We have recently defined the stem-cell-like subpopulation of T-cells that can be reinvigorated by PD-1 targeted therapy,” said senior author Rahfi Ahmed, PhD. “Now we demonstrate that in addition to PD-1 blockade, these cells also require co-stimulatory signals through CD28 to proliferate and differentiate into killer cells. We believe this increase in the number of killer cells is important for successful immunotherapy.”

The team believes their findings may pave the way for studies evaluating CD28 as a biomarker that may help identify patients likely to respond to immune checkpoint inhibitors. It may also lead to the development of combination therapies that enhance the effectiveness of PD-1 inhibitors.