Mesencephalic astrocyte-derived neurotrophic factor is secreted from interferon-γ-activated tumor cells through ER calcium depletion

The most successful immunotherapeutic agents are blocking antibodies to either programmed cell death-1 (PD-1), an inhibitory receptor expressed on T lymphocytes, or to its ligand, programmed cell death-ligand 1 (PD-L1). Nevertheless, many patients do not respond, and additional approaches, specifically blocking other inhibitory receptors on T cells, are being explored. Importantly, the source of the ligands for these receptors are often the tumor cells. Indeed, cancer cells express high levels of PD-L1 upon stimulation with interferon-gamma (IFN-gamma), a major cytokine in the tumor microenvironment. The increase in PD-L1 expression serves as a negative feedback towards the immune system, and allows the tumor to evade the attack of immune cells. A potential novel immunoregulator is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER)-resident protein that is secreted from pancreatic beta cells upon cytokines activation, and can induce an alternatively activated macrophage phenotype (M2), and thus may support tumor growth. While MANF was shown to be secreted from pancreatic beta cells, its IFN-gamma-induced secretion from tumor cells has never been assessed. Here we found that IFN-gamma induced MANF secretion from diverse tumor cell-lines-melanoma cells, colon carcinoma cells and hepatoma cells. Mechanistically, there was no increase in MANF RNA or intracellular protein levels upon IFN-gamma stimulation. However, IFN-gamma induced ER calcium depletion, which was necessary for MANF secretion, as Dantrolene, an inhibitor of ER calcium release, prevented its secretion. Thus, MANF is secreted from IFN-gamma-stimulated tumor cells, and further studies are required to assess its potential as a drug target for cancer immunotherapy.

Automated summary

The successful immunotherapeutic agents target PD-1 or PD-L1, but many patients do not respond well. Research shows that IFN-gamma stimulation not only increases PD-L1 expression in tumor cells, but also induces the secretion of a potential immunoregulator, MANF, which may impact cancer immunotherapy. Further studies are needed to explore the potential of MANF as a drug target for cancer immunotherapy.