NCOA4-Mediated Ferritinophagy: A Potential Link to Neurodegeneration

NCOA4 (Nuclear receptor coactivator 4) mediates the selective autophagic degradation of ferritin, the cellular cytosolic iron storage complex, thereby playing a critical role in intracellular and systemic iron homeostasis. Disruptions in iron homeostasis and autophagy are observed in several neurodegenerative disorders raising the possibility that NCOA4-mediated ferritinophagy links these two observations and may underlie, in part, the pathophysiology of neurodegeneration. Here, we review the available evidence detailing the molecular mechanisms of NCOA4-mediated ferritinophagy and recent studies examining its role in systemic iron homeostasis and erythropoiesis. We propose additional studies to examine the potential role of NCOA4 in the brain in the context of neurodegenerative diseases

Differential effects of inhibitors of the PI3K/mTOR pathway on the expansion and functionality of regulatory T cells

AbstractThe PI3K/mTOR pathway is commonly deregulated in cancer. mTOR inhibitors are registered for the treatment of several solid tumors and novel inhibitors are explored clinically. Notably, this pathway also plays an important role in immunoregulation. While mTOR inhibitors block cell cycle progression of conventional T cells (Tconv), they also result in the expansion of CD4+CD25hiFOXP3+ regulatory T cells (Tregs), and this likely limits their clinical antitumor efficacy. Here, we compared the effects of dual mTOR/PI3K inhibition (using BEZ235) to single PI3K (using BKM120) or mTOR inhibition (using rapamycin and everolimus) on Treg expansion and functionality. Whereas rapamycin, everolimus and BEZ235 effected a relative expansion benefit for Tregs and increased their overall suppressive activity, BKM120 allowed for similar expansion rates of Tregs and Tconv without altering their overall suppressive activity. Therefore, PI3K inhibition alone might offer antitumor efficacy without the detrimental selective expansion of Tregs associated with mTOR inhibition

cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes.

Loss of MHC class I and IFNγ sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. The cellular (c)-IAPs regulate classical and alternative NF-κB signaling. Induction of non-canonical NF-κB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We now show that induction of non-canonical NF-κB signaling induces T cell-dependent immune responses even in β2m-/- tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild type mice, but not mice incapable of antigen-specific T cell responses, IAP antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Activation of non-canonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade due to loss of MHC class I or IFNγ sensing