Uncovering how a molecule responsible for immune “brakes” directs skin defenses

(Press-News.org) Weill Cornell Medicine researchers have discovered that PD-1—a molecule best known for putting the brakes on immune cells—also plays a critical role in helping T cells become long-term immune defenders in the skin. Early during infection, PD-1 acts like a steering wheel, guiding T cells to become protective resident memory T cells (TRM) that stay in place. These cells remember invading germs or cancer and quickly mount a response if that enemy reappears.

The preclinical findings, published July 29 in Nature Immunology, may impact how clinicians approach cancer treatments called immune check point inhibitors. These drugs bind to PD-1 on the surface of T cells, releasing the brakes and unleashing the immune system to attack cancer cells. Though immune check point inhibitors are successful in treating melanoma, an aggressive skin cancer, about 40% of patients develop inflammatory rashes and itching in the skin or reactions in other epithelial tissues that cover internal and external surfaces of the body.

“We observed that PD-1 is required for memory T cells to develop and anchor in skin, putting them in the right spot to have a role in side effects,” said senior author Dr. Niroshana Anandasabapathy, associate professor of dermatology in microbiology and immunology at Weill Cornell Medicine. The study challenges the current understanding of PD-1 as just suppressing immune responses and uncovers a new role as actively promoting the development of TRM.

First authors Sanjana P. Devi, now at Quest Diagnostics, and Eric Wang, now an M.D./Ph.D. student at the University of Pennsylvania, also co-led this research.

Forming Memories and Hanging On

“Resident memory T cells have been reported to express PD-1, yet its exact role in their biology was largely unknown,” said Wang. Dr. Anandasabathy’s team is uniquely positioned to unravel the connection. The lab investigates how immune cells like TRM communicate and work together with other immune cells to recognize and fight cancer, while avoiding harmful overreactions.

When the researchers blocked PD-1 in mice with an antibody against the protein or used T cells genetically modified to remove PD-1, they noticed that the T cells in the skin didn’t develop memory or become anchored in place very early after infection. “We showed genetically, pharmacologically and with imaging that you need PD-1 to form resident memory T cells,” said Dr. Anandasabapathy, who is also a dermatologist at NewYork-Presbyterian/Weill Cornell Medical Center and a member of the Sandra and Edward Meyer Cancer Center.

Genomics data suggested that a cytokine called TGF-β could also be involved in the memory-forming process. Cytokines are messenger molecules that signal growth, movement and activity of other cells, especially those involved in the immune response.

The researchers focused on how TGF-β might be working with PD-1. They demonstrated in mice that when PD-1 activity was blocked early in an infection, TGF-β could be added to rescue the ability of T cells to become TRM cells. “TGF-β signaling is required for resident memory cells in some sites like in the skin and lungs, but not all sites,” Dr. Anandasabapathy said. “PD-1 strongly selects the resident memory T cells that stay in the skin by helping them use TGF-β.” The problem is when PD-1 is blocked too early as in cancer treatment, TRM cells might not form, potentially causing side effects.

Helping Patients

“These results could guide the development of better therapies targeting PD-1 without unwanted side effects for cancer patients,” said Devi. Beyond anti-PD1 cancer therapy, the work has implications for cell therapy treatments for autoimmune patients.

“Some strategies block PD-1 very early, which may unintentionally disrupt TRM cell formation—we need to think about blocking PD-1 in the right context, in a timed way,” said Dr. Anandasabapathy.

END