Molecular signaling in the tumor microenvironment (TME) is complex, and crosstalks among various cell compartments in supporting metastasis remain poorly understood. In particular, the role of vascular pericytes, a critical cellular component in the TME, in cancer invasion and metastasis warrants further investigation. Here we report an elevation of FGF-2 signaling in both nasopharyngeal carcinoma (NPC) patient samples and xenograft mouse models promotes NPC metastasis. Mechanistically, tumor cell-derived FGF-2 strongly promoted pericyte proliferation and pericyte-specific expression of an orphan chemokine (C-X-C motif) ligand 14 (CXCL14) via FGFR1- AHR signaling. Gain and loss-of-function experiments validated that pericyte-derived CXCL14 promoted macrophage recruitment and polarization towards an M2-like phenotype. Genetic knockdown of FGF2 or genetic depletion of tumoral pericytes blocked CXCL14 expression and tumor-associated macrophage (TAM) infiltration. Pharmacological inhibition of TAMs by clodronate liposomes treatment resulted in a reduction of FGF-2-induced pulmonary metastasis. Together, these findings shed light on the inflammatory role of tumoral pericytes in promoting TAM-mediated metastasis. We provide mechanistic insight into an FGF-2-FGFR1-pericyte-CXCL14-TAM stromal communication axis in NPC and propose an effective anti-metastasis therapy concept by targeting a pericyte-derived inflammation for NPC or FGF-2-high tumors.
Yujie Wang, Qi Sun, Ying Ye, Xiaoting Sun, Sisi Xie, Yuhang Zhan, Jian Song, Xiaoqin Fan, Bin Zhang, Ming Yang, Lei Lv, Kayoko Hosaka, Yunlong Yang, Guohui Nie
T cells play a prominent role in orchestrating the adaptive immune response to viral diseases and are a key component in understanding variability in SARS-CoV-2 infection severity and immunity. How the T cell response to SARS-CoV-2 infection and vaccination relates to clinical presentation, other components of the immune response, and subsequent immunity remains poorly understood. A population-based swab survey of the municipality of Vo’, Italy, conducted after the initial SARS-CoV-2 outbreak, uncovered a high frequency of asymptomatic infected individuals and their role in transmission. We sampled the T-cell receptor repertoire structure of the entire Vo’ population 2 months after the initial survey and followed up positive cases at 9 and 15 months post infection. We found that 97.0% (98/101) of cases had elevated levels of T-cell receptors associated with SARS-CoV-2 antigens at 2 months. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the T-cell receptor repertoire were also positively associated with neutralizing antibody titers, driven mostly by helper CD4+ T cells directed towards antigens from spike protein. At the later time points, detection of SARS-CoV-2 associated T cells remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Notably, at 9 months, T-cell signal was detectable in 84.6% (22/26) of cases who were initially asymptomatic. Forty-three individuals had been vaccinated by month fifteen, all presenting with a positive T-cell signal and showing a significant increase in T cells, specifically directed against spike protein. Taken together, these results demonstrate the central role of the T-cell response in mounting a comprehensive immune defense against SARS-CoV-2 that persists out to 15 months.
Rachel M. Gittelman, Enrico Lavezzo, Thomas M. Snyder, H. Jabran Zahid, Cara L. Carty, Rebecca Elyanow, Sudeb C. Dalai, Ilan Kirsch, Lance Baldo, Laura Manuto, Elisa Franchin, Claudia Del Vecchio, Monia Pacenti, Caterina Boldrin, Margherita Cattai, Francesca Saluzzo, Andrea Padoan, Mario Plebani, Fabio Simeoni, Jessica Bordini, Nicola I. Lorè, Dejan Lazarević, Daniela Maria Cirillo, Paolo Ghia, Stefano Toppo, Jonathan M. Carlson, Harlan S. Robins, Andrea Crisanti, Giovanni Tonon
Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway creating an urgent need for novel therapeutic targets. To unbiasedly find novel MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found protein arginine N-methyltransferase 5 (PRMT5) inhibitors to trigger a MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirm the increased efficacy of PRMT5 inhibitors in MYC deregulated PDACs. Although inhibition of PRMT5 is inducing DNA-damage and arresting PDAC cells in the G2/M-phase of the cell cycle, apoptotic cell death was executed predominantly in cells with high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.
Felix Orben, Katharina Lankes, Christian Schneeweis, Zonera Hassan, Hannah Jakubowsky, Lukas Krauß, Fabio Boniolo, Carolin Schneider, Arlett P.G. Schäfer, Janine Murr, Christoph Schlag, Bo Kong, Rupert Öllinger, Chengdong Wang, Georg Beyer, Ujjwal Mukund Mahajan, Yonggan Xue, Julia Mayerle, Roland M. Schmid, Bernhard Kuster, Roland Rad, Christian J. Braun, Matthias Wirth, Maximilian Reichert, Dieter Saur, Günter Schneider
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with limited treatment options. The role of the developmental transcription factor Sine Oculis homeobox homolog 1 (SIX1) in the pathophysiology of lung fibrosis is not known. IPF lung tissue samples and IPF-derived alveolar type II cells (AT2) showed a significant increase in SIX1 mRNA and protein levels, and the SIX1 transcriptional co-activators EYA1 and EYA2 were elevated. Six1 was also upregulated in bleomycin (BLM)-treated mice and in a model of spontaneous lung fibrosis driven by deletion of Telomeric Repeat Binding Factor 1 (Trf1) in AT2 cells. Conditional deletion of Six1 in AT2 cells prevented or halted BLM-induced lung fibrosis as measured by a significant reduction in histological burden of fibrosis, reduced fibrotic mediator expression and improved lung function. These effects were associated with increased macrophage migration inhibitory factor (MIF) in lung epithelial cells in vivo following SIX1 overexpression in BLM-induced fibrosis. A MIF promoter-driven luciferase assay demonstrated direct binding of Six1 to the 5’-TCAGG-3’ consensus sequence of the MIF promoter, identifying a likely mechanism of SIX1-driven MIF expression in the pathogenesis of lung fibrosis, and providing a novel pathway for targeting in IPF therapy.
Cory Wilson, Tinne C.J. Mertens, Pooja Shivshankar, Weizen Bi, Scott D. Collum, Nancy Wareing, Junsuk Ko, Tingting Weng, Ram P. Naikawadi, Paul J. Wolters, Pascal Maire, Soma S.K. Jyothula, Rajarajan A. Thandavarayan, Dewei Ren, Nathan D. Elrod, Eric J. Wagner, Howard J. Huang, Burton F. Dickey, Heide L. Ford, Harry Karmouty-Quintana
Pain emanating from the female reproductive tract is notoriously difficult to be treated and the prevalence of transient pelvic pain has been placed as high as 70-80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here we show that the pain-initiating TRPA1 channel is required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2- and 4-hydroxylated estrogen metabolites (HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol and 16-HEMs, directly increase nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2- and 4-hydroxylation estrone (OHE1) can sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 are expressed in uterine-innervating primary nociceptors and their expressions are increased in the estrogen-induced uterine pain model. Importantly, pretreatment of 2- or 4-OHE1 recapitulates estrogen-induced uterine pain-like behaviors and intraplantar injections of 2- and 4-OHE1 directly produce a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrate that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain.
Zili Xie, Jing Feng, Tao Cai, Ronald McCarthy, Mark D. Eschbach II, Yuhui Wang, Yonghui Zhao, Zhihua Yi, Kaikai Zang, Yi Yuan, Xueming Hu, Fengxian Li, Qin Liu, Aditi Das, Sarah K. England, Hongzhen Hu
Sex/gender disparity in asthma is recognized, and suggests a modulatory role for sex-steroids, particularly estrogen. However, studies including our own show a dichotomous role for estrogen in airway remodeling, making it unclear whether sex hormones are protective or detrimental in asthma, and suggesting a need to explore mechanisms upstream or independent of estrogen. We hypothesize that Kisspeptin (Kp)/KISS1R signaling serves this role. Airway smooth muscle (ASM) is a key structural cell type that contributes to remodeling in asthma. We explored the role of Kp/KISS1R in regulating ASM proliferation. We report novel data that Kp and KISS1R are expressed in human airways, especially ASM, with lower expression in ASM from females compared to males, and asthmatics showing lowest expression compared to non-asthmatics. Proliferation studies showed that cleaved forms of Kp, particularly Kp-10 mitigates PDGF-induced ASM proliferation. Pharmacological inhibition and shRNA knockdown of KISS1R increased basal ASM proliferation, further amplified by PDGF. The anti-proliferative effect of Kp-10 in ASM was found to be mediated by inhibition of MAPK-ERK-Akt pathways, with altered expression of PCNA, C/EBP-alpha, Ki-67, Cyclin-D1, and Cyclin-E leading to cell-cycle arrest at G0/G1 phase. Overall, we demonstrate the importance of Kp/KISS1R signaling in regulating ASM proliferation and a potentially novel therapeutic avenue to blunt remodeling in asthma.
Niyati A. Borkar, Nilesh Sudhakar Ambhore, Rama Satyanarayana Raju Kalidhindi, Christina M. Pabelick, Y.S. Prakash, Venkatachalem Sathish
A major challenge in managing acute viral infections is ameliorating disease when treatment is delayed. Previously, we reported the success of a two-pronged monoclonal antibody (mAb) and antiviral remdesivir therapeutic approach to treat advanced illness in Marburg virus (MARV)-infected rhesus monkeys. Here, we explored the benefit of a similar combination therapy for Sudan ebolavirus (SUDV) infection. Importantly, no licensed anti-SUDV therapeutics currently exist, and infection of rhesus macaques with SUDV results in a rapid disease course similar to MARV with a mean time-to-death of 8.3 days. When initiation of therapy with either remdesivir or a pan ebolavirus mAb cocktail (MBP431) was delayed until 6 days post inoculation (dpi), only 20% of macaques survived. In contrast, when remdesivir and MBP431 treatment were combined beginning 6 dpi, significant protection (80%) was achieved. Our results suggest that combination therapy may be a viable treatment for patients with advanced filovirus disease that warrants further clinical testing in future outbreaks.
Robert W. Cross, Zachary A. Bornholdt, Abhishek N. Prasad, Courtney Woolsey, Viktoriya Borisevich, Krystle N. Agans, Daniel J. Deer, Dafna M. Abelson, Do H. Kim, William S. Shestowsky, Lioudmila A. Campbell, Elaine Bunyan, Joan B. Geisbert, Natalie S. Dobias, Karla A. Fenton, Danielle P. Porter, Larry Zeitlin, Thomas W. Geisbert
Elucidating how resident enteric bacteria interact with their hosts to promote health or inflammation is of central importance to diarrheal and inflammatory bowel diseases across species. Here, we integrate the microbial and chemical microenvironment of a patient’s ileal mucosa with their clinical phenotype and genotype to identify factors favoring the growth and virulence of Adherent and Invasive E. coli (AIEC) linked to Crohn’s disease. We determine that the ileal niche of AIEC is characterized by inflammation, dysbiosis, coculture of Enterococcus and oxidative stress. We discover that mucosal metabolites support general growth of ileal E. coli, with a selective effect of ethanolamine on AIEC that is augmented by co-metabolism of ileitis-associated amino acids and glutathione, and symbiosis-associated fucose. This metabolic plasticity is facilitated by the eut and pdu microcompartments, amino acid metabolism, γ-glutamyl-cycle and pleotropic stress responses. We link metabolism to virulence, finding that ethanolamine and glutamine enhance AIEC motility, infectivity and pro-inflammatory responses in vitro. We connect use of ethanolamine to intestinal inflammation, and L-fuculose phosphate aldolase (fucA) to symbiosis in AIEC mono-associated IL10-/- mice. Collectively, we establish that AIEC are pathoadapted to utilize mucosal metabolites associated with health and inflammation for growth and virulence, enabling the transition from symbiont to pathogen in a susceptible host.
Shiying Zhang, Xochitl C, Morgan, Belgin Dogan, Francois-Pierre Martin, Susan R. Strickler, Akihiko Oka, Jeremy Herzog, Bo Liu, Scot E. Dowd, Curtis Huttenhower, Matthieu Pichaud, Esra I. Dogan, Jack Satsangi, Randy Longman, Rhonda Yantiss, Lukas A. Mueller, Ellen Scherl, R. Balfour Sartor, Kenneth W. Simpson
Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases, and its findings might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify non-small cell lung cancer (NSCLC) patients who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis were compared regarding therapeutic effect in 12 patients. Compared to ICI non-responders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti-PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and their balance could contribute to nivolumab sensitivity in NSCLC patients. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.
Kentaro Masuhiro, Motohiro Tamiya, Kosuke Fujimoto, Shohei Koyama, Yujiro Naito, Akio Osa, Takashi Hirai, Hidekazu Suzuki, Norio Okamoto, Takayuki Shiroyama, Kazumi Nishino, Yuichi Adachi, Takuro Nii, Yumi Kinugasa-Katayama, Akiko Kajihara, Takayoshi Morita, Seiya Imoto, Satoshi Uematsu, Takuma Irie, Daisuke Okuzaki, Taiki Aoshi, Yoshito Takeda, Toru Kumagai, Tomonori Hirashima, Atsushi Kumanogoh
BACKGROUND. Breakthrough SARS-CoV-2 infections in vaccinated individuals have been previously associated with suboptimal humoral immunity. However, less is known about breakthrough infections with the Omicron variant. METHODS. We analyzed SARS-CoV-2 specific antibody and cellular responses in healthy vaccine recipients who experienced breakthrough infections a median of 50 days after receiving a booster mRNA vaccine with an ACE2 binding inhibition assay and an ELISpot assay respectively.Results: We found high levels of antibodies that inhibited vaccine strain spike protein binding to ACE2 but lower levels that inhibited Omicron variant spike protein binding to ACE2 in four boosted vaccine recipients prior to infection. The levels of antibodies that inhibited vaccine strain and Omicron spike protein binding after breakthrough in 18 boosted vaccine recipients were similar to levels seen in COVID-19 negative boosted vaccine recipients. In contrast, boosted vaccine recipients had significantly stronger T cells responses to both vaccine strain and Omicron variant spike proteins at the time of breakthrough. CONCLUSIONS. Our data suggest that breakthrough infections with the Omicron variant can occur despite robust immune responses to the vaccine strain spike protein. FUNDING. This work was supported by the Johns Hopkins COVID-19 Vaccine-related Research Fund and by funds from the National Institute of Allergy and Infectious Disease intramural program as well as awards from the National Cancer Institute (U54CA260491) and the National Institutes of Allergy and Infectious Disease (K08AI156021 and U01AI138897)
Bezawit A. Woldemeskel, Caroline C. Garliss, Tihitina Y. Aytenfisu, Trevor S. Johnston, Evan J. Beck, Arbor G. Dykema, Nicole Frumento, Desiree A. Wright, Andrew H. Yang, Alexander I. Damanakis, Oliver Laeyendecker, Andrea L. Cox, Heba H. Mostafa, Andrew H. Karaba, Joel N. Blankson
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