T cell revival through PD-1: Clues for cancer immunotherapy

August 2, 2016
Spleen of LCMV-infected mouse. The population of PD-1-responsive T cells is CD8+ and TCF1+ and thus appears as yellow. Credit: From Im et al. Nature (2016)

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

Scientists from Emory Vaccine Center have now shown what molecular features distinguish the subset of T cells that wake up when re-energized by PD-1-blocking agents.

The researchers expect that their findings will be valuable for optimizing treatment with PD-1-targeting drugs. The experiments were performed in mice with , the system in which T cell exhaustion and PD-1's immune-braking function were first discovered.

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

PD-1-blocking agents such as nivolumab, pembrolizumab and atezolizumab are part of a class of drugs known as checkpoint inhibitors, and many cancer researchers are now trying to figure out how to enhance their activity by combining them with other types of drugs.

"If we know more about the markers on the T cells that expand after PD-1's inhibition is removed, that could facilitate the rational design of combination therapies," says senior author Rafi Ahmed, PhD, director of Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

The first author of the Nature paper is postdoctoral fellow Sejin Im, PhD. Collaborators from NIAID (National Institute of Allergy and Infectious Diseases), University of Iowa, Harvard Medical School, Dana Farber Cancer Institute and University of São Paolo, Brazil contributed to the paper.

More than a decade ago, Ahmed and colleagues had shown that the immune systems of mice with chronic viral infections were full of inactive, or "exhausted" antiviral T cells. These cells displayed high levels of PD-1, and antiviral activity could be revived if PD-1's interactions with its counterpart on other cells (PD-L1) were blocked.

In the current paper, the authors demonstrate that the exhausted antiviral T cells can be divided into two groups. One group undergoes a proliferative burst when virus-infected mice are given PD-1-blocking antibodies, and the other group lacks the capacity to proliferate.

Even before PD-1-blocking antibodies were introduced, the expandable group of virus-specific T cells was dividing at a slow rate. These cells were only in the T cell zones of lymphoid organs (lymph nodes and spleen), not circulating throughout the body. After PD-1 is blocked, these cells divide and differentiate into effector-like cells that migrate to infected tissues.

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

The researchers also showed 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 that resembled memory T cells or stem-like cells, while the non-responsive T cells were more terminally differentiated.

The authors catalogued several co-stimulatory molecules and receptors present on the surfaces of the PD-1-responsive T cells, which possibly could be targets for drugs.

In collaboration with researchers at Winship Cancer Institute of Emory University, Ahmed's laboratory is looking for with similar characteristics in cancer patients. It is possible that this group of revivable T may be found in contact with the tumor, or perhaps more likely, in lymph nodes nearby, Ahmed says.

Explore further: Immunotherapy agent can disrupt viral reservoir in SIV-infected monkeys

Related Stories

Immunotherapy agent can disrupt viral reservoir in SIV-infected monkeys

February 25, 2016
An immune-enhancing treatment can push SIV (simian immunodeficiency virus) out of its hideouts in infected monkeys that have the virus controlled with drugs, scientists at Yerkes National Primate Research Center, Emory University ...

Study reveals protein that dials immune responses up and down

May 26, 2016
Research led by scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) has identified a new regulator of immune responses. The study, published recently in Immunity, sheds new light on why T cells fail ...

Immune 'traffic jam' from viral infection interferes with therapeutic antibodies

February 12, 2015
Several drugs now used to treat cancer and autoimmune diseases are actually repurposed tools derived from the immune system. One of the ways these "therapeutic antibodies" work is to grab onto malignant or inflammatory cells ...

'Pep talk' can revive immune cells exhausted by chronic viral infection

December 13, 2011
Chronic infections by viruses such as HIV or hepatitis C eventually take hold because they wear the immune system out, a phenomenon immunologists describe as exhaustion.

Vaccine blackjack: IL-21 critical to fight against viral infections

May 23, 2013
(Medical Xpress)—Scientists at Emory Vaccine Center have shown that an immune regulatory molecule called IL-21 is needed for long-lasting antibody responses in mice against viral infections.

Recommended for you

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.