Researchers find link between stress-activated signaling and immune cell evasion in melanoma

Anti-cancer immune cells are critical for inhibiting the development and progression of tumors, and deregulation of the immune system can limit the ability of immune cells to identify and target cancer cells for destruction. Cancer cells are also exposed to various environmental stresses that affect their survival, such as nutrient deprivation, low oxygen levels, and anticancer treatments. To continue to survive and overcome these stresses, cancer cells activate survival signaling pathways. PERK is a protein that is activated during stress-induced signaling, but it is not known how PERK activation in cancer cells promotes immune cell evasion.

Moffitt Cancer Center researchers wanted to determine how PERK activity affects clinical outcomes in melanoma patients. They found that patients with high PERK activity had a shorter overall survival than patients with low PERK activity. Similarly, patients with higher PERK activity had worse immunotherapy outcomes and lower levels of antitumor immune cells than patients with lower PERK activity.

These observations indicate that PERK may promote survival and influence the activity of immune cells in melanoma patients. The authors confirmed this hypothesis in mouse models of melanoma; inhibition of PERK is reduced tumor growth in mice, which depended on the antitumor activity of immune cells. Their results are published in a new article in Cancer cell.

The researchers conducted a series of laboratory experiments to determine the mechanism by which PERK controls immune cells in melanoma. They found that inhibiting PERK promotes a type of cell death called paraptosis, which involves swelling of the endoplasmic reticulum and mitochondria and the development of fluid-containing vesicles in the cell’s cytoplasm. These cell death-related immune effects were dependent on type I interferon proteins. Signaling through the type I interferon receptor during PERK inhibition resulted in immune cell trafficking to tumors and allowed immature immune cells mature into dendritic cells that trigger antitumor T-cell immunity.

“Taken together, our results demonstrate a key role for PERK signaling in tumor cells while evading protective immunity. Although these findings are primarily melanoma, other tumor types may have similar susceptibility to PERK-targeted therapy,” explained Paulo Rodríguez, Ph.D., Moffitt’s Interim Head of Immunology.