Stress-activated signalling and immune cell evasion in melanoma

Anti-cancer immune cells are essential for preventing the development and progression of tumours, and immune system dysregulation can impair their ability to identify and destroy cancer cells. In addition to nutritional scarcity, low oxygen levels, and anti-cancer therapy, cancer cells are exposed to a variety of environmental factors that affect their survival. Cancer cells activate survival signalling pathways to continue surviving and overcome these challenges. Stress-induced signalling activates the PERK protein, however it is unknown how PERK activation in cancer cells contributes to immune cell evasion.

Researchers at the Moffitt Cancer Center aimed to determine how PERK activity influences the clinical outcomes of melanoma patients. They found that patients with high PERK activity had a shorter overall survival rate than those with low PERK activity. Patients with higher PERK activity had worse immunotherapy outcomes and lower numbers of anti-tumor immune cells than those with lower PERK activity.

These findings imply that PERK may improve survival and influence immune cell function in melanoma patients. In mouse models of melanoma, the authors supported this idea; suppression of PERK reduced tumour growth in mice, which was dependent on the anti-tumor activity of immune cells. Their findings are detailed in a recent Cancer Cell publication.

Researchers conducted a series of laboratory tests to establish how PERK regulates immune cells in melanoma. They discovered that PERK inhibition promotes a kind of cell death known as paraptosis, which involves swelling of the endoplasmic reticulum and mitochondria, as well as the formation of fluid-containing vesicles in the cytoplasm. These immunological actions linked with cell death were dependent on type I interferon proteins. Signaling through interferon type I receptor during PERK suppression led in immune cell transportation to tumours and the maturation of immature immune cells into dendritic cells, which stimulated anti-tumor T cell immunity.


Journal Reference

Jessica K. Mandula et al, Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses, Cancer Cell (2022). DOI: 10.1016/j.ccell.2022.08.016

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