Study uncovers how tumors exploit a molecular signal to exhaust T cells

A new study has discovered a molecular signal that tumors exploit to exhaust the T cells meant to destroy them-and how silencing that signal could revive the body's immunity. The study led by Weill Cornell Medicine researchers was published Nov. 17 in Nature Immunology and shows that tumors not only evade the immune system but can actively reprogram immune cells to stop fighting.

"Our dream is to make immune-based therapies available to every patient. To overcome resistance, we must unlock the power of exhausted T cells, reviving them to destroy cancer. This discovery moves us closer to a future where the immune system itself defeats tumors," said the study's co-senior author, Dr. Taha Merghoub, Margaret and Herman Sokol Professor in Oncology Research, and professor of pharmacology at Weill Cornell Medicine.

In recent years, immunotherapy has transformed cancer care, offering a way to rally the body's own immune system to fight tumors. But even with these advances, many patients still don't respond-or their initial response fades as their immune cells become exhausted.

Our findings reveal a completely new way that tumors suppress the immune system. By blocking this pathway, we can help exhausted T cells recover their strength and make existing immunotherapies work better for more patients."

Dr. Jedd Wolchok, co-senior author, the Meyer Director of the Sandra and Edward Meyer Cancer Center, professor of medicine, Weill Cornell and oncologist at NewYork-Presbyterian/Weill Cornell Medical Center

Keeping the immune system fighting

T cell exhaustion is a phenomenon triggered by continued exposure to chronic infections or tumors that activate the immune system. The embattled immune cells remain capable of recognizing their foes, but they no longer attack them. "So, they're primed, but they're no longer killing," said Dr. Merghoub, who is also deputy director of the Meyer Cancer Center and co-director of the Parker Institute of Cancer Immunotherapy at Weill Cornell. "Although such cellular surrender may seem counterproductive, it serves as a brake to protect against out-of-control inflammation and sepsis," Dr. Merghoub said.

Previous work from other labs has demonstrated that a protein called PD1 on the surface of T cells plays a key role in putting the brakes on T cells. Checkpoint-inhibitor drugs, which target PD1, have been remarkably successful in reviving T cells to treat cancers such as melanomas. 

Looking for another set of brakes

The researchers started out investigating whether CD47 molecules present on cancer cells contributed to T cell exhaustion. Previous studies showed that tumors can use CD47 to instruct the immune cells that normally engulf invaders to stand down-a skill that prompted its nickname as a "don't eat me signal."

But they were surprised to discover that CD47 has another function on the surface of T cells. "When T cells are activated, they express CD47. And when they get exhausted, they increase CD47 to very high levels," Dr. Merghoub said.

Their experiments found that mice lacking CD47 had delayed tumor growth. This suggested CD47 on the animal's immune cells, not the CD47 on the cancer cells, was causing exhaustion. They suspected that eliminating CD47 on T cells could be beneficial. When tested in mice with melanoma, T cells lacking CD47 were better at fighting the cancer than T cells, which had CD47 intact.

The researchers turned their attention to how the cancer cells coopted T-cell CD47 to promote exhaustion. They focused on a large protein called thrombospondin-1 that interacts with CD47 and is produced by metastatic cancer cells. When they tested mice lacking thrombospondin-1, they found that T cells were less exhausted. "That was the real eureka moment," said Dr. Merghoub. "It showed us that CD47 and thrombospondin are clearly key players because eliminating either one gives you the same effect."

Targeting an exhausting interaction

To better understand what was happening, the researchers used the TAX2 peptide that was designed to selectively disrupt the interaction between CD47 and thrombospondin-1 in their mouse tumor models. Their suspicions were confirmed: TAX2 preserved T-cell function and slowed down tumor progression in mice with melanoma or colorectal tumors.

The T cells in treated mice stayed more active, produced more immune boosting cytokines and were better at infiltrating tumors. In addition, TAX2 worked in synergy with PD-1 immunotherapy in controlling colorectal tumor growth.

"We used the TAX2 peptide as a proof-of-concept to confirm that disrupting the crosstalk between TSP-1 and CD47 prevents T cell exhaustion in mice with tumors," said Dr. Chien-Huan (Gil) Weng, an instructor in pharmacology and the study's lead author. "Next, we plan to study both upstream and downstream modulators that regulate the TSP-1:CD47 pathway and develop means to selectively, effectively and safely disrupt this pathway to improve T cell-based cancer immunotherapy."

Targeting this interaction would be a valuable therapeutic on its own, but it could also help preserve tumor-reactive T cells in patients who would otherwise develop resistance to the currently available T cell-based immune checkpoint inhibitors. Even more promising, experiments in preclinical tumor models suggest that blocking both PD1 and CD47 produces T cells that are more effective at killing cancer cells, Dr. Merghoub said. "We plan to explore this therapeutic angle."