Taking the itch out of cancer immunotherapy

October 26, 2020

Tsukuba, Japan - Using the body's immune system to fight cancer has great potential, but can also bring serious side effects, including itchy and painful skin reactions. But now, researchers from Japan have found how these skin reactions happen, potentially leading to a way to prevent them.

In a study published this month in Communications Biology, researchers from the University of Tsukuba have determined that one unpleasant side effect of immunotherapy with PD-1 inhibitors, called "anti-PD-1 antibody-induced psoriasis-like dermatitis," is caused by inflammation resulting from high levels of a specific protein. Cancer immunotherapies work through a process that allows the body's T cells to recognize and attack cancers. But because these same processes regulate inflammation, things can get out of balance.

Therapies targeting PD-1 often lead to side effects called immune-related adverse events (irAEs), which happen in more than 70% of patients who take them. The most common of these is a skin reaction, and while some of these are mild and can be easily treated with steroid creams, other patients have itchy, painful, or scaly rashes requiring more intensive treatment. Nearly a fifth of patients receiving immunotherapy stop taking the treatment because of irAEs--even though the treatment may be working well against their cancer.

"Inhibition of the PD-1 pathway is becoming front-line treatment for more and more cancers," says senior author Professor Naoko Okiyama. "But it can't work if patients experience adverse events and discontinue treatment because of them. We hoped that by finding out exactly how PD-1 inhibitors cause dermatitis, we could also find a way to stop it."

The new study builds on earlier research from the same team, who examined blood samples from cancer patients with this side effect, finding high levels of a cell signaling protein called IL-6. Testing this theoretical connection in mice, they found that PD-1 deficiency increased numbers of a specific type of white blood cells (called CD8 T cells) infiltrating the epidermis. CD8 T cells help the immune system kill viruses and bacteria as well as cancer cells. But when activated in large numbers, they can cause an excessive immune response leading to irAEs.

The experiments in mice showed that PD-1 expressed on CD8 T cells regulates skin inflammation. The mice with PD-1 deficiency had high levels of IL-6 expression and subsequently developed dermatitis. As a final step, the researchers used an antibody to block IL-6 signaling in some of these mice--and those mice developed significantly less dermatitis than the control group.

"Altogether, the results clearly show the efficacy of targeting IL-6 in mice," explains Professor Okiyama. "With further study in humans, we may have a potential approach to resolving PD-1-related dermatitis."

On the basis of these results, the researchers also propose that blockade of both IL-6 and PD-1 together could have an even better combined anti-cancer effect, though this has not yet been systematically studied. It's also unknown whether the approach will work as well in people as it does in mice.

"Our most striking finding is the importance of PD-1 expression on CD8 T cells in the development of dermatitis, showing real potential of IL-6 as a target for therapeutic intervention," says Professor Okiyama. "But the hope is that we can implement this combined strategy without compromising the anti-tumor effects of the anti-PD-1 therapy."

Immunotherapies for cancer treatment are still relatively new; therefore, limited information is available on their long-term side effects in comparison with older chemotherapy treatments. As increasing numbers of cancer patients are treated with anti-PD-1 immunotherapy, it will be ever more important to identify strategies to prevent or lessen these adverse events.
The article, "Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6," was published in Communications Biology at DOI: 10.1038/s42003-020-01308-2.

University of Tsukuba

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

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.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.