Hu et al. report that TDO2+ myofibroblasts in the tumor microenvironment shield tumor cells from T cell attack, induce transformation of CD4+ T cells into Tregs, and cause CD8+ T cell dysfunction.
Prevalent copy number alteration (CNA) is the most prominent genetic characteristic associated with ovarian cancer (OV) development, but its role in immune evasion has not been fully elucidated. In this study, we identified RAD21, a key component of the cohesin complex, as a frequently amplified oncogene that could modulate immnue response in OV. Through interrogating RAD21-regulated transcriptional program we found that RAD21 directly interacts with YAP/TEAD4 transcriptional co-repressors and recruits NuRD complex to suppress interferon (IFN) signaling. In multiple clinical cohorts, RAD21 overexpression is inversely correlated with IFN signature gene expression in OV. We further demonstrated in murine syngeneic tumor models that RAD21 ablation potentiated anti-PD-1 efficacy with increased intratumoral CD8+ T-cell effector activity. Our study identified a previously unrecognized RAD21-YAP/TEAD4-NuRD co-repressor complex in immune modulation, and thus provided a potential target and biomarker for precision immunotherapy in OV.
Peng Deng, Zining Wang, Jinghong Chen, Shini Liu, Xiaosai Yao, Shaoyan Liu, Lizhen Liu, Zhaoliang Yu, Yulin Huang, Zhongtang Xiong, Rong Xiao, Jiuping Gao, Weiting Liang, Jieping Chen, Hui Liu, Jing Han Hong, Jason Yongsheng Chan, Peiyong Guan, Jianfeng Chen, Yali Wang, Jiaxin Yin, Jundong Li, Min Zheng, Chao Zhang, Penghui Zhou, Tiebang Kang, Bin Tean Teh, Qiang Yu, Zhixiang Zuo, Qingping Jiang, Jihong Liu, Ying Xiong, Xiaojun Xia, Jing Tan
The various functions of the skeleton are influenced by extracellular cues, hormones and neurotransmitters. One type of neuronal regulation favors bone mass accrual by inhibiting sympathetic nervous system activity. This observation raises questions about the transcriptional mechanisms regulating catecholamine synthesis. Using a combination of genetic and pharmacological studies we have found that the histone deacetylase SIRT1 is a transcriptional modulator of the neuronal control of bone mass. Neuronal SIRT1 reduced bone mass by increasing SNS signaling. SIRT1 did so by increasing expression of monoamine oxidase A (MAO-A), a SIRT1 target that reduces brain serotonin levels by inducing its catabolism, and by suppressing Tph2 expression and serotonin synthesis in the brainstem. SIRT1 upregulated brain catecholamine synthesis indirectly through serotonin but did not directly affect Dbh expression in the locus coeruleus. These results help understand skeletal changes associated with SSRIs and may have implications for treating skeletal and metabolic diseases.
Na Luo, Ioanna Mosialou, Mattia Capulli, Brygida Bisikirska, Chyuan-Sheng Lin, Yung-yu Huang, Peter Timothy Shyu, X. Edward Guo, Aris Economides, J. John Mann, Stavroula Kousteni
Platelets and megakaryocytes are critical players in immune responses. Recent reports suggest infection and inflammation alter the megakaryocyte and platelet transcriptome to induce altered platelet reactivity. We examined if non-viral sepsis induces differential platelet gene expression and reactivity. Non-viral sepsis upregulated IFITM3, an interferon responsive gene that restricts viral replication. As IFITM3 has been linked to clathrin-mediated endocytosis, we examined if IFITM3 promoted endocytosis of alpha granule proteins. Interferon stimulation enhanced fibrinogen endocytosis in megakaryocytes and platelets from Ifitm+/+ mice, but not Ifitm-/- mice. IFITM3 overexpression or deletion in megakaryocytes demonstrated IFITM3 was necessary and sufficient to regulate fibrinogen endocytosis. Mechanistically, IFITM3 interacts with clathrin and αIIb and altered their plasma membrane localization into lipid rafts. In vivo interferon administration increased fibrinogen endocytosis, platelet reactivity, and thrombosis in an IFITM-dependent manner. In contrast, Ifitm-/- mice were completely rescued from interferon-induced platelet hyperreactivity and thrombosis. During murine sepsis, platelets from Ifitm+/+ mice demonstrated increased fibrinogen content and platelet reactivity, which was dependent on interferon-alpha and IFITMs. Platelets from patients with non-viral sepsis had increases in platelet IFITM3 expression, fibrinogen content, and hyperreactivity. These data identify IFITM3 as a regulator of platelet endocytosis, hyperreactivity, and thrombosis during inflammatory stress.
Robert A. Campbell, Bhanu Kanth Manne, Meenakshi Banerjee, Elizabeth A. Middleton, Abigail Ajanel, Hansjorg Schwertz, Frederik Denorme, Chris Stubben, Emilie Montenont, Samantha Saperstein, Lauren Page, Neal D. Tolley, Diana L. Lim, Samuel M. Brown, Colin K. Grissom, Douglas W. Sborov, Anandi Krishnan, Matthew T. Rondina
People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the PLAUR gene (rs4760) confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, Pcsk9 transfection in mice over-expressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared to wild-type mice, despite similar cholesterol levels. Pre-atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared to wild-type aortas. Aortic and circulating suPARTg monocytes exhibited a pro-inflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
George Hindy, Daniel J. Tyrrell, Alexi Vasbinder, Changli Wei, Feriel Presswalla, Hui Wang, Pennelope K. Blakely, Ayse Bilge Ozel, Sarah E. Graham, Grace H. Holton, Joseph Dowsett, Akl C. Fahed, Kingsley-Michael Amadi, Grace K. Erne, Annika Tekumulla, Anis Ismail, Christopher Launius, Nona Sotoodehnia, James S. Pankow, Lise Wegner Thørner, Christian Erikstrup, Ole Birger Pedersen, Karina Banasik, Søren Brunak, Henrik Ullum, Jesper Eugen-Olsen, Sisse Rye Ostrowski, Mary E. Haas, Jonas B. Nielsen, Luca A. Lotta, Gunnar Engström, Olle Melander, Marju Orho-Melander, Lili Zhao, Venkatesh L. Murthy, David J. Pinsky, Cristen J. Willer, Susan R. Heckbert, Jochen Reiser, Daniel R. Goldstein, Karl C. Desch, Salim S. Hayek
Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and was driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicted downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance could be overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and re-sensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.
Laura A. Sena, Rajendra Kumar, David E. Sanin, Elizabeth A. Thompson, D. Marc Rosen, Susan L. Dalrymple, Lizamma Antony, Yuhan Yang, Carolina Gomes-Alexandre, Jessica L. Hicks, Tracy Jones, Kiara A. Bowers, Jillian N. Eskra, Jennifer Meyers, Anuj Gupta, Alyza Skaist, Srinivasan Yegnasubramanian, Jun Luo, W. Nathaniel Brennen, Sushant K. Kachhap, Emmanuel S. Antonarakis, Angelo M. De Marzo, John T. Isaacs, Mark C. Markowski, Samuel R. Denmeade
JCI This Month is a digest of the research, reviews, and other features published each month.
Aging plays a central role in many chronic diseases affecting all systems of the body. Nine hallmarks of aging have been identified: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. This new review series on Aging closely examines how these hallmarks contribute to the initiation and progression of disease. Curated by series editor Dr. James Kirkland, topics span aging’s role in immune system function, cancer, cognitive decline and neurodegenerative disease, and metabolism. The reviews also discuss the latest developments in senotherapeutic strategies that destroy senescent cells, reverse senescence, or target specific aging hallmarks with a critical eye.