A brand new examine has found a molecular sign that tumors exploit to exhaust the T cells meant to destroy them-and how silencing that sign may revive the physique’s immunity. The examine led by Weill Cornell Medicine researchers was printed Nov. 17 in Nature Immunology and exhibits that tumors not solely evade the immune system however can actively reprogram immune cells to cease combating.
“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,” mentioned the examine’s co-senior writer, Dr. Taha Merghoub, Margaret and Herman Sokol Professor in Oncology Research, and professor of pharmacology at Weill Cornell Medicine.
In latest years, immunotherapy has remodeled most cancers care, providing a technique to rally the physique’s personal immune system to struggle tumors. But even with these advances, many sufferers nonetheless do not respond-or their preliminary response fades as their immune cells grow to be exhausted.
Our findings reveal a totally new method that tumors suppress the immune system. By blocking this pathway, we can assist exhausted T cells get better their energy and make current immunotherapies work higher for extra sufferers.”
Dr. Jedd Wolchok, co-senior writer, the Meyer Director of the Sandra and Edward Meyer Cancer Center, professor of drugs, Weill Cornell and oncologist at NewYork-Presbyterian/Weill Cornell Medical Center
Keeping the immune system combating
T cell exhaustion is a phenomenon triggered by continued publicity to power infections or tumors that activate the immune system. The embattled immune cells stay able to recognizing their foes, however they now not assault them. “So, they’re primed, but they’re no longer killing,” mentioned Dr. Merghoub, who can also be 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 mentioned.
Previous work from different labs has demonstrated {that a} protein known as PD1 on the floor of T cells performs a key position in placing the brakes on T cells. Checkpoint-inhibitor medication, which goal PD1, have been remarkably profitable in reviving T cells to deal with cancers comparable to melanomas.
Looking for an additional set of brakes
The researchers began out investigating whether or not CD47 molecules current on most cancers cells contributed to T cell exhaustion. Previous research confirmed that tumors can use CD47 to instruct the immune cells that usually engulf invaders to face down-a talent that prompted its nickname as a “don’t eat me signal.”
But they have been shocked to find that CD47 has one other operate on the floor 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 mentioned.
Their experiments discovered that mice missing CD47 had delayed tumor development. This instructed CD47 on the animal’s immune cells, not the CD47 on the most cancers cells, was inflicting exhaustion. They suspected that eliminating CD47 on T cells may very well be useful. When examined in mice with melanoma, T cells missing CD47 have been higher at combating the most cancers than T cells, which had CD47 intact.
The researchers turned their consideration to how the most cancers cells coopted T-cell CD47 to advertise exhaustion. They centered on a big protein known as thrombospondin-1 that interacts with CD47 and is produced by metastatic most cancers cells. When they examined mice missing thrombospondin-1, they discovered that T cells have been much less exhausted. “That was the real eureka moment,” mentioned 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 interplay
To higher perceive what was occurring, the researchers used the TAX2 peptide that was designed to selectively disrupt the interplay between CD47 and thrombospondin-1 of their mouse tumor fashions. Their suspicions have been confirmed: TAX2 preserved T-cell operate and slowed down tumor development in mice with melanoma or colorectal tumors.
The T cells in handled mice stayed extra energetic, produced extra immune boosting cytokines and have been higher at infiltrating tumors. In addition, TAX2 labored in synergy with PD-1 immunotherapy in controlling colorectal tumor development.
“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,” mentioned Dr. Chien-Huan (Gil) Weng, an teacher in pharmacology and the examine’s lead writer. “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 interplay could be a beneficial therapeutic by itself, but it surely may additionally assist protect tumor-reactive T cells in sufferers who would in any other case develop resistance to the at the moment out there T cell-based immune checkpoint inhibitors. Even extra promising, experiments in preclinical tumor fashions recommend that blocking each PD1 and CD47 produces T cells which can be more practical at killing most cancers cells, Dr. Merghoub mentioned. “We plan to explore this therapeutic angle.”
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Journal reference:
Weng, C. -H., et al. (2025). Thrombospondin-1–CD47 signaling contributes to the event of T cell exhaustion in most cancers. Nature Immunology. doi: 10.1038/s41590-025-02321-5.