Researchers at Johns Hopkins University have discovered that variations in gene expression levels can provide insight into mechanisms that allow tumors to respond to immunotherapies.
The study, “Transcriptional Mechanisms of Resistance to Anti–PD-1 Therapy,” was published in the journal Clinical Cancer Research.
Scientists have been working to create drugs called immunotherapies which manipulate the immune system as a defense mechanism against cancer. These drugs can initiate an immune response in patients that is specifically targeted toward cancer cells.
One type of immunotherapy currently being investigated are known as checkpoint inhibitors. They function to stop tumor cells from evading the immune system.
While these therapies are successful in some cancers, they don’t work with all cancers. In fact, they don’t consistently work in all patients with the same type of cancer.
One well-known checkpoint inhibitor called anti-PD-1 (programmed cell death-1) works in 60 percent of patients with advanced Hodgkin’s lymphoma, but works in only 20 percent of patients with lung, bladder, and head and neck cancer.
PD-1 is a protein whose expression is increased by tumor cells as it allows them to evade the immune system. Anti-PD-1 is an immunotherapy which helps the immune system recognize the presence of tumor cells, which then works to kill them.
Anti-PD-1 has recently been approved for the treatment of metastatic melanoma, Hodgkin’s lymphoma, and lung, kidney, bladder, and head and neck cancers.
To determine the cause of the difference in response rates to these checkpoint inhibitors, researchers analyzed 26 different melanoma tumors obtained from one 60-year-old patient with metastatic melanoma that was treated with anti-PD-1 until he died from a non-cancer-related cause. The autopsy allowed physicians to conduct an analysis of these tumors.
Over the course of treatment, CT scans revealed that some of the tumors in the patient were responding to the therapy and shrinking, but others were completely non-responsive.
This prompted researchers to conduct two different tests on the tumor samples, whole exome sequencing and assessing immunologic markers. Whole exome sequencing refers to a process that helps determine if there are mutations in the genetic sequence for genes that are expressed. Assessing immunologic markers allows researchers to determine the immune response in patients by analyzing immune cells and molecules.
Interestingly, neither of these tests showed a difference between the tumors that responded to anti-PD-1 and those that didn’t.
This caused researchers to conduct a different test called gene expression analysis, which allowed them to look at how many copies of a gene are being produced in the different tumors, indicating gene activity. This was a successful strategy, as the researchers discovered that there was a marked difference in gene activity between the responding and non-responding tumors.
Results from this test showed that 13 different genes were expressed differently in the responsive and unresponsive tumors. Among them, the tumors that were not sensitive to anti-PD-1 treatment had a 2,000-fold higher activity in the LAMA3 gene. The unresponsive tumors also had four-times more activity in the gene CXCR2.
LAMA3 is involved in helping normal and cancer cells migrate, and CXCR2 is involved in melanoma cell growth and plays a role in attracting immune cells to sites of inflammation.
Data from this study could be used to develop new drugs or improve the use of current checkpoint inhibitors and other immunotherapeutic drugs.
“We conclude that gene expression analysis is a potentially powerful tool for discovering the Achilles heel for each tumor,” Dr. Suzanne Topalian, MD, a professor in the Department of Surgery at the Johns Hopkins University School of Medicine, said in a press release.
