T cells PD-1-sensitive may offer clues to design more effective drugs for cancer

T cells PD-1-sensitive may offer clues to design more effective drugs for cancer -

cancer immunotherapy drugs that block the PD-1 pathway inhibitor have shown success in clinical trials and are now approved by the FDA for melanoma, lung cancer and bladder cancer. Yet many patients tumors do not respond to these drugs.

Scientists at Emory Vaccine Center have now shown what are the molecular characteristics distinguish the subset of T cells that wake when reinvigorated by PD-1 blocking agents.

The researchers expect their results will be useful to optimize the treatment of PD-1-targeting drugs. The experiments were performed in mice with chronic viral infections, the system wherein the depletion of T cells and immune function of PD-1 were discovered braking.

The results are scheduled for publication online Nature at 11 am Eastern Time Tuesday, August 2.

PD-1 blocking agents such as nivolumab, pembrolizumab atezolizumab and are part of a class of drugs called checkpoint inhibitors, and many cancer researchers are now trying to understand how to improve their business by combining with other types of drugs.

"If we know more about the markers on T cells that increase after the PD-1 inhibition is removed, which could facilitate rational design of combination therapies," says lead author Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

the first author of the Nature paper are postdoctoral fellow Sejin Im, PhD. Employees NIAID (National Institute of Allergy and Infectious Diseases), University of Iowa, Harvard Medical School, Dana-Farber Cancer Institute and the University of São Paulo, Brazil contributed to the paper.

More than a decade ago, Ahmed and his colleagues showed that the immune system in mice with chronic viral infections were full of inactive or antiviral T cells "exhausted". These cells had high levels of PD-1, and antiviral activity could be revived if PD-1 interactions with his counterpart on other cells (PD-L1) were blocked.

In this paper, the authors demonstrate that the antiviral T cell exhaustion can be divided into two groups. One group underwent a proliferative burst when mice infected with the virus are given PD-1 antibody-blocker, and the other group has no capacity to proliferate.

Even before blocking PD-1 antibody were introduced, the extensible group

specific T cell of the virus was split at a slow speed. These cells were only in the lymphoid organs areas (lymph nodes and spleen) T lymphocytes, does not circulate in the body. After PD-1 is blocked, these cells divide and differentiate into effector cells such as migrating to infected tissues

"If you imagine a chronic viral infection -. Or cancer - such as war, expandable T cells are not in the intense part of the battle, "said Ahmed. "But they are not engaged. It's like they're waiting in a shelter, ready to answer."

The researchers have also shown that a gene called TCF1 was important for the generation and maintenance of the PD-1-responsive T cells in mice. Inside and outside, the PD-1-responsive cells had molecular characteristics resembling similar memory T cells or stem cells, whereas non-responsive T cells were more terminal differentiation.

The authors cataloged several costimulatory molecules and receptors present on the surfaces of T cells PD-1-sensitive, which could be targets for drugs.

In collaboration with researchers at Winship Cancer Institute of Emory University, laboratory Ahmed is looking to immune cells with similar characteristics in patients with cancer. It is possible that this group of T viable cells can be found in contact with the tumor, or perhaps more likely, in nearby lymph nodes, said Ahmed.