New Clues About Why Certain Skin Cancers Vary Among Patients

Genetic studies of the skin cancer called cutaneous T-cell lymphoma uncover the first steps toward new treatments tailored for patients’ specific subtypes.

Grantee: Jaehyuk Choi, MD, PhD
Institution: Northwestern University Feinberg School of Medicine in Chicago, IL
Area of Study: Biochemistry and Immunology of Cancer
Grant Term: 09/01/2020 to 8/31/2024

“Research funded by the American Cancer Society has enabled my lab to take one step closer to precision medicine for this potentially devastating disease. We can identify the molecular features that make skin lymphomas more dangerous. The goal now is to identify novel drugs to target this aggressive disease subtype.”

The Challenge: T-cells are a type of immune cell. T-cell lymphomas are a collection of different cancers of T cells. When a cancer-causing T-cell moves to the skin, it’s called cutaneous T-cell lymphoma (CTCL), skin lymphoma, or non-Hodgkin lymphoma of the skin. It’s not common, and it cannot be cured.

Many patients with CTCL have itchy, scaly patches skin, which can often look like eczema or psoriasis, making the condition sometimes hard to diagnose. It can be treated with ointments, light therapy, chemotherapy, radiation therapy, and sometimes stem cell transplants. See pictures of skin lymphomas.

Plus, patients can have very diverse symptoms and disease outcomes. For instance, people diagnosed with stage IV disease may live less than 6 months or more than 20 years.

Because CTCL can vary so much in different patients, not much is understood about how the disease is caused at the cellular level.

The Research: ACS Research Scholar Grantee and physician scientist, Jaehyuk Choi, MD, PhD, and team collected more than 300 CTCL samples from patients with different stages of disease, subtypes, and symptoms. Those samples allowed them to analyze more than previous CTCL studies, which tended to focus on only one subtype of the cancer and with older gene sequencing techniques.

To better understand how CTCL works, the researchers gathered three types of data: gene sequences, genes that are turned on and off, and cell characteristics.

Their analysis identified 86 driver genes, which are the genes whose mutations cause tumor growth. This included 19 genes that had not previously been linked with the disease. They also discovered 2 genetic mutations that have never been described in any cancer.

And to their surprise, they found 1 gene had a much stronger association with worse outcomes than the rest—PD1.

In a healthy, nonmutated state, the PD1 gene helps prevent overactivity of T-cells and autoimmunity—where the immune system attacks the body. In other types of cancer, blocking PD1 helps recruit more T cells to fight cancer. But Choi’s team found that when the cancer starts in T-cells, as with CTCL, shutting down PD1 causes the cancer to get worse.

Why it Matters: Some cancers are treated with immunotherapies that suppress the PD1 receptor to unleash the body’s immune system against cancer, but this study demonstrates that CTCLs may be a poor candidate for that type of immunotherapy.

Choi’s discovery of PD1’s effect and other gene mutations associated with this type of skin cancer may allow scientists to develop new treatments that are tailored to a patient’s genome.