PaperReading
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IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion
Li-Chuan Chan,Chia-Wei Li...Shao-Chun Wang,and Mien-Chie Hunget al
JCI
Hepatocellular carcinoma (HCC) has long been a difficult disease to treat. We know, glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression in HCC patient remains unclear. In this paper, the authors identified IL-6–activated JAK1 phosphorylates programmed death-ligand 1(PD-L1) Tyr112, which recruits the endoplasmic reticulum–associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1stability. Firstly,to identify the signaling pathways that potentially affect the glycosylation and stabilization of PD-L1 in HCC, the authors selected pathwaysbased on the following 3 criteria: (a) cytokine levels areincreased in HCC patients with poor prognosis and are able to upregulate PD-L1 protein expression because PD-L1 glycosylation affects PD-L1 protein stability; (b)downstream tyrosine (Tyr) and Ser/Thr kinases interact directly with PD-L1, particularly those for which therapeutic inhibitors are approved and whose activities are blocked by these inhibitors; and (c) activatingmutations are reported in HCC. So, they intended to screen for HCC-related cytokines that may upregulate PD-L1 protein expression. Moreover, to further validate the IL-6 and PD-L1 relationship in human HCC tumors, the authors analyzed the correlation between IL-6 and PD-L1 expression in 183 HCC patient tumor tissues.And found that patients with high IL-6expression also had elevated PD-L1 expression in tumors. In addition, they identified that STT3A are essential for PD-L1 glycosylation and protein stabilization. Next, they found that phosphorylation of PD-L1 Y112 enhancesSTT3A association with PD-L1 and maintains PD-L1 stability.what is more, targeting of IL-6 by IL-6 antibody-inducedsynergistic T cell killing effects when combined with anti–T cell immunoglobulin mucin-3(anti–Tim-3) therapy in animal models.
All in all, treatment with immune checkpoint inhibitors has been shown to stimulate the production of IL-6 in serum, which can cause psoriasiform dermatitis, arthritis, and Crohn’s disease in cancer patients. Therefore, blocking the IL-6pathway may resolve these side effects and extend the duration of immunotherapy.
/10.1172/JCI126022
02
Oncogene Amplification in Growth Factor Signaling
Pathways Renders Cancers Dependent on Membrane Lipid Remodeling
Junfeng Bi,Taka-Aki Ichu,CiroZanca,...Benjamin F. Cravatt,and Paul S. Mischel et al
Cell Metabolism
Cancer is a process of unrestrained cell division. Receptors on the surface of cells frequently become genetically altered, existing as oncogenic receptors and sending signals that drive unrestrained cell division, leading to tumor formation and cancerprogression. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood.
In this paper, the authors initially sought to identify lipid-modifying enzymes that could integrate persistent growth factor receptor signaling with plasma membrane remodeling by examining the impact of constitutive EGFR signaling on phospholipid composition in a simple cancer cell line model. Then they demonstrated that LPCAT1 is a critical co-dependency target in EGFRvIIIamplified GBMs, but also noted the high frequency of LPCAT1 amplification organ in many other cancer types. They further confirm that PC32:0, PC28:0, andPC30:0 are LPCAT1 products and demonstrate that LPCAT1-derived saturated PCsare required for tumor growth. All in all, these results point to agenotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.
/10.1016/j.cmet..06.014
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