Researchers at Mayo Clinic have discovered why certain cases of lung adenocarcinoma respond well to immunotherapy. In a new study published in Cell Reports, researchers have identified several previously unknown genetic and cellular processes that occur in lung adenocarcinoma tumors that respond well to immunotherapy. A group of recently approved drugs — immune checkpoint inhibitors — can boost the body's ability to eliminate a tumor and prevent its recurrence. However, while these treatments work remarkably well in some people, they are not effective for many other cases — and researchers are trying to figure out why. The Dr. Fields lab at Mayo Clinic in Florida has been studying the PRKCI gene, which drives tumor growth, for years. The research team observed that the absence of the gene that drives the tumor, known as PRKCI, leads to less aggressive tumors. The first experiments showed that tumors without PRKCI grow less aggressively. The collaborating labs were surprised to find that senescent tumor cells actually activate the immune system, leading to clusters of immune cells that fight the tumor. The absence of this gene also favors a more intense immune response against the tumor. This gene also reduces the activity of the immune system, keeping defense cells capable of destroying cancer at bay. “We discovered that the loss of PRKCI forces tumor cells to co-opt a lung regeneration mechanism to form a tumor,” explains Nguyen. The team also observed that tumors without PRKCI showed high levels of organized clusters of immune cells, known as tertiary lymphoid structures. The study also identified markers that could predict a favorable response to immunotherapy and that “in the long run may help clinicians better select those who might benefit from immune checkpoint inhibitors,” says Joey Nguyen, a graduate student in the Mayo Clinic Graduate School of Biomedical Sciences and lead author of the publication. “The idea that senescent cells could be beneficial in certain contexts like this is novel to the field, as these 'zombies' are usually associated with detrimental effects of diseases and aging,” says Dr. Baker, corresponding author of the study. The findings reveal three tumor characteristics that can be used to help doctors identify candidates for immune checkpoint inhibitors: the absence of the PRKCI gene, the presence of senescent tumor cells, and a high concentration of grouped immune cells. Furthermore, explains Dr. Fields, his team had previously identified a drug already approved that can block PRKCI signaling, causing a tumor that has the gene to behave more like a tumor that lacks it. “Now that we understand how PRKCI acts in a lung tumor, it may be possible to combine a PRKCI inhibitor with immunotherapy, so a future clinical trial integrating these strategies will undoubtedly be an important avenue to explore,” he states.
