Mayo Clinic uncovers novel biomarkers for lung adenocarcinoma treatment success
Lung adenocarcinoma is the most common form of lung cancer and can occur in both smokers and people who have never smoked.
UAE—Researchers at Mayo Clinic have identified genetic and cellular processes that may help explain why some patients with lung adenocarcinoma respond better to immunotherapy than others.
Published in Cell Reports, the study examined tumors with a missing copy of PRKCI, a gene that promotes tumor growth and suppresses immune activity.
The researchers found that tumors lacking one copy of the gene were less aggressive and showed stronger immune activity.
PRKCI loss alters tumor development
Lung adenocarcinoma is the most common form of lung cancer and can occur in both smokers and people who have never smoked.
Although immune checkpoint inhibitors can help the immune system recognize and destroy cancer cells, they do not benefit all patients.
Alan P. Fields, Ph.D., a cancer biologist at Mayo Clinic Comprehensive Cancer Center, said the study focused on tumors carrying only one copy of PRKCI, a genetic alteration found in about 20% of lung adenocarcinoma cases.
The researchers found that tumors with a missing PRKCI copy developed less aggressively.
At an early stage, the cancer cells also acquired characteristics associated with lung cells involved in tissue repair.
Working with systems biology researcher Hu Li, Ph.D., the team examined the tumors at the single-cell level.
The analysis showed that PRKCI loss causes tumor cells to activate a process normally involved in regenerating damaged lung tissue.
Senescent cells trigger immune activity
The researchers also observed higher levels of tertiary lymphoid structures, which are organized clusters of immune cells associated with immune activity against tumors.
This finding led the team to investigate whether another cellular process could explain the increased immune response.
Postdoctoral researcher Luis Prieto, Ph.D., proposed that the structures could be linked to senescent tumor cells, which stop dividing but remain metabolically active.
Researchers from Prieto’s team and the laboratory of Darren Baker, Ph.D., then examined the role of these cells.
They found that senescent tumor cells activated immune responses that contributed to the formation of tertiary lymphoid structures around the tumors.
Baker said senescent cells are generally associated with harmful effects in disease and aging, making their immune-stimulating role in these tumors unexpected.
Potential markers for immunotherapy
The study identified three tumor characteristics that could help researchers assess potential responses to immune checkpoint inhibitors: loss of one copy of PRKCI, the presence of senescent tumor cells and increased tertiary lymphoid structures.
Joey Nguyen, a graduate student at Mayo Clinic Graduate School of Biomedical Sciences and the study’s lead author, said these markers could eventually help clinicians identify patients who may benefit from immune checkpoint treatment.
Fields’ laboratory has also previously identified an approved drug that can inhibit PRKCI signaling.
According to Fields, blocking this pathway could make tumors that retain PRKCI behave more like tumors that have lost one copy of the gene.
The researchers are now considering whether combining a PRKCI inhibitor with immunotherapy could support future clinical studies.
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