Role of PD-1 in skin immune readiness clarified

Dr. Niroshana Anandasabapathy. Photo courtesy Weill Cornell Medicine

Researchers have discovered that the immune-regulating molecule programmed cell death protein 1 (PD-1) plays a critical role in helping T cells become long-term immune defenders in the skin. They say this knowledge may help reduce the side effects of anti-PD-1 treatments for skin cancer in the future.

The findings were published in Nature Immunology (2025; 26:1,339–1,351).

The investigators, from Weill Cornell Medicine in New York, discovered that PD-1 guides immune T cells to become protective resident memory T cells (TRM) that stay in place in the skin, remembering antigens from prior disease or cancer cells to support the immune system in quickly mounting a response if that threat reappears. However, PD-1 also plays a role in allowing the immune system to recognize the body’s cells, a feature that some cancers exploit to avoid detection and destruction.

Researchers say their preclinical findings may impact how clinicians approach cancer treatments using immune checkpoint inhibitors. These medications bind to PD-1 on the surface of T cells, inhibiting the immune suppression and allowing the system to attack cancer cells. They write that while immune checkpoint inhibitors are successful in treating melanoma, approximately 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, in a press release. Dr. Anandasabapathy is an associate professor of Dermatology in Microbiology and Immunology at Weill Cornell Medicine.

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

“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 lab investigates how immune cells such as 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 New York-Presbyterian/Weill Cornell Medical Center and a member of the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. 

Genomics data suggested that a cytokine called TGF-β could also be involved in the memory-forming process.

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 signalling is required for resident memory cells in some sites, like 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.

“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.