Missing cancer gene may boost response to immunotherapy

For some patients with the most common type of lung cancer, known as lung adenocarcinoma, there's new hope. In a new study published in Cell Reports, Mayo Clinic researchers have found several previously unknown genetic and cellular processes that occur in lung adenocarcinoma tumors that respond well to immunotherapy.

A recently approved group of drugs - immune checkpoint inhibitors - can boost the body's ability to eliminate a tumor and even keep the cancer from coming back. However, while the medications work well for some people, the drugs aren't effective for many other patients with the disease - and researchers are trying to determine why. 

Our study describes the events that occur when a patient's tumor harbors only one copy of a cancer-causing gene, which occurs in 20% of cases." 

Alan P. Fields, Ph.D., cancer biologist at Mayo Clinic Comprehensive Cancer Center and principal investigator of the study

The research team found that the missing tumor-driving gene, known as PRKCI, results in tumors that are less aggressive. The missing gene also cultivates a more powerful immune response to tumors. Surprisingly, the research team found the improved immune response occurs with help from unexpected players: senescent tumor cells, also known as "zombie cells," which are typically associated with negative consequences of disease and aging. 

The study identified markers that may predict a positive response to immunotherapy and "ultimately may help clinicians stratify patients who are candidates for immune checkpoint inhibitors," says Joey Nguyen, a graduate student at Mayo Clinic Graduate School of Biomedical Sciences and lead author of the publication. 

Addressing the nation's leading cause of cancer death

Lung adenocarcinoma represents 40% of lung cancers in the U.S. and is the leading cause of cancer death. It's strongly associated with smoking, but it's also the most common type of lung cancer to occur in people who have never smoked, likely because of a combination of genetics and other environmental factors. 

Dr. Fields' lab at Mayo Clinic in Florida has long studied the effect of the PRKCI gene, which drives tumor growth. The gene also suppresses the immune system, keeping cancer-killing immune cells at bay. Because lung tumors depend on the gene to proliferate, Dr. Fields' team was surprised to find that in cases where a copy of the gene is missing, lung adenocarcinoma tumors still occur. Nguyen, who was studying PRKCI in the lab, was inspired to try to learn more about those unusual tumors. 

Early experiments found that the tumors without PRKCI grow less aggressively. The team also found that when PRKCI is missing, lung adenocarcinoma cells behave in an unusual way in their very early development, acquiring characteristics of lung cells that regenerate lung tissue after damage. 

The team collaborated with the lab of systems biology researcher Hu Li, Ph.D., to examine the process at a single cell level. "We found that the loss of PRKCI forces tumor cells to hijack a lung regeneration process to generate a tumor," Nguyen says. 

Tracking the effects of a missing gene

Nguyen also noticed that the tumors without PRKCI showed elevated levels of organized clusters of immune cells, called tertiary lymphoid structures. The presence of those clumped cells can be a sign that immune checkpoint therapy might work for a patient. But were they a result of the single copy of the PRKCI gene? 

Nguyen presented his research at a graduate school seminar where the project caught the attention of postdoctoral fellow Luis Prieto, Ph.D., who had an idea. Dr. Prieto wondered whether the clusters of immune cells might be connected in some way to senescent cells, those that enter a state of arrested development and don't die off. Dr. Prieto works in the lab of researcher Darren Baker, Ph.D., who investigates therapies to eliminate senescent cells in various disease processes.

The collaborating labs were amazed to find that senescent tumor cells actually activate the immune system, leading to the clusters of immune cells that combat the tumor. "The idea that senescent cells may be beneficial in certain settings like this is new to the field, as these 'zombies' are commonly associated with detrimental outcomes," says Dr. Baker, who is a co-corresponding author on the study.

The findings reveal three tumor characteristics that may be used to help clinicians identify candidates for immune checkpoint inhibitors: loss of the PRKCI gene, the presence of senescent tumor cells and an abundance of clustered immune cells. 

Further, says Dr. Fields, his team previously identified an approved drug that can inhibit PRKCI signaling, making a tumor that has the PRKCI gene act more like a tumor without it. 

"Now that we understand how PRKCI is working in a lung tumor, it may be possible to couple a PRKCI inhibitor with immunotherapy, so a future clinical trial that combines these approaches will certainly be an important avenue to explore," he says.