Nav: Home

Increasing the effectiveness of cancer treatments: Anti-PD-L1 immunotherapy

September 18, 2020

An international research team of Tokyo Medical and Dental University (TMDU) and Harvard Medical School (HMS) has discovered that controlling the nuclear localization of the PD-L1 immune checkpoint protein can enhance the efficacy of immunotherapy for cancer treatment

Tokyo, Japan - For most people, there is no scarier diagnosis than that of cancer. While treatments including chemotherapy and radiotherapy have been used since the 1940s and late 1800s, respectively, immunotherapy has more recently emerged as a viable and successful approach to cancer treatment. Indeed, evasion of the host immune system is an essential feature of tumorigenesis. Figuring out how cells do this, and disrupting it, to allow the patient's own immune system to eliminate the cancer cells, is the basis of immunotherapy.

In a study published in August 2020 in Nature Cell Biology, a team including researchers from Tokyo Medical and Dental University (TMDU) and Harvard Medical School (HMS) have identified the regulatory mechanisms through which the PD-L1 immune check-point protein dictates the efficacy of anti-PD-L1 immunotherapy.

"We already knew that immunotherapies targeting immune-checkpoint inhibitors were somewhat successful in treating some cancer types," says co-author Naoe Taira Nihira. "However, only a subset of patients achieved long-lasting results."

PD-L1 expression is tightly controlled, and patients with increased PD-L1 expression in tumors are likely to respond well to PD-L1 blockade; however, the reasons why increased PD-L1 expression leads to increased PD-L1 blockade sensitivity have remained unclear. The research team examined a specific kind of PD-L1 modification, called acetylation, and found that removal of this modification allows PD-L1 to enter the nucleus and interact with DNA to regulate the immune response.

Using a variety of advanced molecular, biochemical, and bioinformatics approaches, the researchers examined PD-L1 acetylation, localization, function, and interactions. They found that plasma membrane localized PD-L1 translocates to the nucleus by interacting with transport pathway components. Specifically, by introducing a series of mutations into PD-L1 and expressing different acetyltransferases, they determined that PD-L1 is acetylated by p300 at a specific residue within the cytoplasm called Lys263. Using similar approaches, and protein depletion by short-interfering RNAs, they also discovered that histone deacetylase (HDAC) specifically interacts with and deacetylates PD-L1.

Protein modifications, including acetylation, can affect protein stability, dimerization, or localization. However, when the team reduced the amount of HDAC2 protein in the cells, consequently increasing the acetylation level, there were no observable changes in protein stability or dimerization. Co-author Akira Nakanishi explains: "These results mean that the acetylation and deacetylation of PD-L1 at this residue play a critical role in its nuclear translocation."

In the nucleus, PD-L1 regulates the expression of pro-inflammatory and immune-response-related genes, indicating that PD-L1 could function to regulate the local tumor immune environment to control its sensitivity to immune checkpoint-blockade therapy .

Given the health and economic burdens of cancer worldwide, new treatment approaches with increased efficacy are continually being sought. The results presented by this team indicate that targeting PD-L1 translocation can be used to enhance the efficacy of PD-1/PD-L1 blockade-based immunotherapy approaches.
The article, "Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy" was published in Nature Cell Biology at DOI: 10.1038/s41556-020-0562-4

Tokyo Medical and Dental University

Related Cancer Articles:

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.
Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.
Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at     You can read The Transition Integrity Project's report here.