Proteomics Identifies New Therapeutic Targets of Early-stage Hepatocellular Carcinoma
Jiang Y, Sun A, Zhao Y, et al. Nature. February 2019.
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer diagnoses and is one of the leading causes of cancer-related deaths worldwide.1,2 In a recent study in Nature led by the Chinese Human Proteome Project Consortium, the proteomic signatures that were associated with early-stage HCC were identified.2 Using this approach, the authors were able to stratify patients into three subtypes: S-I, S-II, and S-III, with S-III representing a subtype with the poorest prognosis.
To analyze the proteomic signatures, primary tumor tissues and adjacent paired nontumor tissues were obtained from the livers of patients with early-stage HCC. The tumour samples exhibited significantly higher protein abundance compared to nontumor tissue; furthermore, higher protein levels were detected in tumor tissues from patients with elevated serum levels of α-fetoprotein and microscopic vascular invasion by HCC cells. Commonly upregulated proteins in early-stage HCC tissues were those associated with the MAPK pathway, PDGF, TNF, MET, and integrins.
Focusing on HCC subtype S-III, the authors found that these patients exhibited a higher degree of α-fetoprotein and microscopic vascular invasion in comparison to other subtypes. These tumors were characterized by a greater infiltration by M2-macrophages and regulatory T cells and displayed proteomic markers of metabolic dysregulation—especially of glycolysis and cholesterol metabolism. An important observation that sterol O-acyltransferase 1 (SOAT1) was upregulated in S-III tumor tissue led the authors to investigate this protein as a potential therapeutic target. SOAT1 has already been associated with high-risk scores for mortality in HCC patients (and is expressed in a diverse range of other cancers),2,3 and its role as a catalyzer in the formation of cholesteryl esters could explain the dysregulation of cholesterol metabolism previously described from proteomic analysis of tumor tissues.2 In the current study, knockdown of SOAT1 altered the distribution of cellular cholesterol, resulting in the suppression of the proliferation and migration of HCC cells. Moreover, inhibition of SOAT1 with avasimibe in a patient-derived tumor xenograft mouse model resulted in a significant reduction in tumor growth in tumors with a high expression of SOAT1.
The approach used by the Consortium in this study demonstrates the power of a personalized approach to therapy based on a specific tumor signature. With the use of extensive proteomic and phosphoproteomic analyses, a therapeutic effect of SOAT1 inhibition in S-III HCC was revealed. SOAT1 appears promising as both a biomarker and a therapeutic target for this specific subtype of HCC, and potentially for many other cancer types in which it has been implicated with a poor prognosis.
1. Dong J-J, Ying L, Shi K-QExpression of the Wnt ligands gene family and its relationship to prognosis in hepatocellular carcinoma. Cancer Cell Int. 2019;19:34.
2. Jiang Y, Sun A, Zhao Y, et alProteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567:257–261.
Uhlen M, Zhang C, Lee S, et alA pathology atlas of the human cancer transcriptome. Science. 2017;357.
Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance While Maintaining Antipathogen Immunity
Jayachandran R, Gumienny A, Bolinger B, et al. Immunity, January 2019.
Finding a balance between preventing transplant rejection and maintaining effective antipathogen and tumor immunity is critical, and one that Jayachandran et al have sought to address in their report featured in Immunity. By interfering with the cAMP-PKA-pCREB pathway, the authors modulated the activity of alloantigen-reactive T cells, while preserving antimicrobial responses.1
Coronin 1, a regulator of the cAMP-PKA-pCREB pathway in T cells, is responsible for increasing levels of phosphodiesterase 4 (PDE4), a kinase which degrades cAMP (cAMP) in T cells.1 cAMP is known to be a negative regulator of T-cell activation, and low intracellular levels of PDE4 are associated with increased cAMP.2 The authors found that deletion of the coronin 1 gene (Coro1a−/−) in mice led to an intracellular increase in cAMP concentration and consequently a selective depletion of peripheral mature naive T cells. MHC-mismatched hearts that were transplanted into Coro1a−/− mice engrafted long-term with minimal vascular changes. The authors then mimicked the effects of intrinsic coronin 1 deficiency by administering the PDE4 inhibitor, rolipram, to reduce cAMP degradation in T cells. To assess whether immunity against microbial pathogens could still be induced, the effects of rolipram on T-cell proliferation in response to either allogeneic APCs or allogeneic APCs presenting Salmonella antigen were compared. While the T-cell response to alloantigen was suppressed by rolipram, the response against Salmonella antigen was not significantly altered, suggesting that targeting the cAMP pathway can preserve protective antimicrobial responses while inducing tolerance to alloantigens. Blockade of the CD80/CD28 pathway abrogated this ability to respond to pathogens, highlighting the importance of costimulation in preserving desired T-cell function.
This study not only demonstrates the importance of the cAMP-PKA-pCREB signalling pathway in the therapeutic modulation of T-cell responses, but also the potential for pharmacological modification of cAMP levels as a method to alter T-cell responses. The approach is innovative in that it spares the direct blockade of costimulatory molecules, leaving them able to engage in T-cell activation in the context of microbial infection, while overall maintaining the desired outcome of allograft tolerance.
1. Jayachandran R, Gumienny A, Bolinger B, et alDisruption of coronin 1 signaling in T cells promotes allograft tolerance while maintaining anti-pathogen immunity. Immunity. 2019;50:152.e8–165.e8.
2. Wehbi VL, Taskén KMolecular mechanisms for camp-mediated immunoregulation in T cells—role of anchored protein kinase A signaling units. Front Immunol. 2016;7:222.