Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses antigen-reactive naïve and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here we dissected heterologous donor-reactive memory CD8 T cell proliferation and their effector functions following infiltration into heart allografts having low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions requires p40 homodimer-induced IL-15 transpresentation by graft dendritic cells, but expression of effector functions mediating acute allograft injury occurs only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8 T cells are distinct from donor antigen-primed memory CD8 T cells during early activation in allografts and at graft rejection. Overall, the results insights into mechanisms driving heterologous effector memory CD8 T cell proliferation and the separation between proliferation and effector function, that is dependent on the intensity of inflammation within the tissue microenvironment.
Hidetoshi Tsuda, Karen S. Keslar, William M. Baldwin III, Peter S. Heeger, Anna Valujskikh, Robert L. Fairchild
Loss of BRCA2 (BReast CAncer 2) is lethal for normal cells. Yet, it remains poorly understood how in BRCA2 mutation carriers, cells undergoing loss of heterozygosity overcome the lethality and undergo tissue-specific neoplastic transformation. Here, we identified mismatch repair gene, MLH1 as a genetic interactor of BRCA2 whose over-expression supports the viability of Brca2-null cells. Mechanistically, we showed that MLH1 interacts with Flap endonuclease 1 (FEN1) and competes to process the RNA flaps of Okazaki fragments. Together, they restrained the DNA2 nuclease activity on the reversed forks of lagging strands, leading to replication fork (RF) stability in BRCA2-deficient cells. In these cells, MLH1 also attenuated R-loops, allowing the progression of stable RFs, which suppressed the genomic instability and supported cell viability. We demonstrated the significance of their genetic interaction by the lethality of Brca2-mutant mice and inhibition of Brca2-deficient tumor growth in mice by Mlh1 loss. Furthermore, we described that estrogen induces MLH1 expression through estrogen receptor alpha (ERα), which might explain why the majority of BRCA2 mutation carriers develop ER positive breast cancer. Taken together, our findings reveal a role of MLH1 in relieving replicative stress and how it may contribute to the establishment of BRCA2-deficient breast tumors.
Satheesh K. Sengodan, Xiaoju Hu, Vaishnavi Peddibhotla, Kuppusamy Balamurugan, Alexander Y. Mitrophanov, Lois McKennett, Suhas S. Kharat, Rahul Sanawar, Vinod Kumar Singh, Mary E. Albaugh, Sandra S. Burkett, Yongmei Zhao, Bao Tran, Tyler Malys, Esta Sterneck, Subhajyoti De, Shyam K. Sharan
BACKGROUND. The tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context, and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC). METHODS. This study involved 2,600 GC patients of nine independent cohorts. We developed and validated two CT imaging biomarkers [lymphoid radiomics score (LRS) and myeloid radiomics score (MRS)] for evaluating the immunohistochemistry (IHC)-derived lymphoid and myeloid immune context respectively, and then integrated them into a combined imaging biomarker [LRS/MRS: low(−) or high(+)] with four radiomics immune subtypes: 1(−/−), 2(+/−), 3(−/+), and 4(+/+). We further evaluated the imaging biomarkers' predictive values on prognosis and immunotherapy response. RESULTS. The developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Furthermore, same as IHC-derived immune context, two imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P<0.05). In addition, patient with high LRS or low MRS may benefit more from immunotherapy (P<0.001). Furthermore, a highly heterogeneous outcome on objective response rate was observed in four imaging subtypes: 1(−/−) with 27.3%, 2(+/−) with 53.3%, 3(−/+) with 10.2%, and 4(+/+) with 30.0% (P<0.0001). CONCLUSION. The noninvasive imaging biomarkers could accurately evaluate the immune context, and provide information regarding prognosis and immunotherapy for GC. FUNDING. None
Zepang Sun, Taojun Zhang, M. Usman Ahmad, Zixia Zhou, Liang Qiu, Kangneng Zhou, Wenjun Xiong, Jingjing Xie, Zhicheng Zhang, Chuanli Chen, Qingyu Yuan, Yan Chen, Wanying Feng, Yikai Xu, Lequan Yu, Wei Wang, Jiang Yu, Guoxin Li, Yuming Jiang
Maggie E. Jones-Carr, Huma Fatima, Vineeta Kumar, Douglas J. Anderson, Julie Houp, Jackson C. Perry, Gavin A. Baker, Leigh McManus, Andrew J. Shunk, Paige M. Porrett, Jayme E. Locke
Breast cancer stem cells (BCSCs) mitigate oxidative stress to maintain their viability and plasticity. However, the regulatory mechanism of oxidative stress in BCSCs remains unclear. We recently found that the histone reader ZMYND8 was upregulated in BCSCs. Here, we showed that ZMYND8 reduced ROS and iron to inhibit ferroptosis in aldehyde dehydrogenase (ALDH)high BCSCs, leading to BCSC expansion and tumor initiation in mice. The underlying mechanism involved a twofold posttranslational regulation of nuclear factor erythroid 2–related factor 2 (NRF2). ZMYND8 increased stability of NRF2 protein through KEAP1 silencing. On the other hand, ZMYND8 interacted with and recruited NRF2 to the promoters of antioxidant genes to enhance gene transcription in mammospheres. NRF2 phenocopied ZMYND8 to enhance BCSC stemness and tumor initiation by inhibiting ROS and ferroptosis. Loss of NRF2 counteracted ZMYND8’s effects on antioxidant genes and ROS in mammospheres. Interestingly, ZMYND8 expression was directly controlled by NRF2 in mammospheres. Collectively, these findings uncover a positive feedback loop that amplifies the antioxidant defense mechanism sustaining BCSC survival and stemness.
Maowu Luo, Lei Bao, Yuanyuan Xue, Ming Zhu, Ashwani Kumar, Chao Xing, Jennifer E Wang, Yingfei Wang, Weibo Luo
Ischemia reperfusion injury (IRI)-mediated primary graft dysfunction (PGD) adversely impacts both short- and long-term outcomes after lung transplantation, a procedure which remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrate by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observe that lung-infiltrating B cells produce the monocyte chemokine CCL7 in Toll-like receptor 4 (TLR4)-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We find that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborate our findings in reperfused human lungs, where we observe a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies.
Khashayar Farahnak, Yun Zhu Bai, Yuhei Yokoyama, Deniz B. Morkan, Zhiyi Liu, Junedh M. Amrute, Alejandro De Filippis Falcon, Yuriko Terada, Fuyi Liao, Wenjun Li, Hailey M. Shepherd, Ramsey R. Hachem, Varun Puri, Kory J. Lavine, Andrew E. Gelman, Ankit Bharat, Daniel Kreisel, Ruben G. Nava
Wnts, cholesterol, and MAPK signaling are essential for development and adult homeostasis. Here we report for the first time that fatty acid hydroxylase domain containing 2 (FAXDC2), a previously uncharacterized enzyme, functions as a methyl sterol oxidase catalyzing C4 demethylation in the Kandutsch-Russell branch of the cholesterol biosynthesis pathway. FAXDC2, a paralog of MSMO1, regulates the abundance of specific C4-methyl sterols lophenol and dihydro-TMAS. Highlighting its clinical relevance, FAXDC2 is repressed in Wnt/β-catenin high cancer xenografts, in a mouse genetic model of Wnt activation, and in human colorectal cancers. Moreover, in primary human colorectal cancers, the sterol lophenol, regulated by FAXDC2, accumulates in the cancerous tissues and not in adjacent normal tissues. FAXDC2 links Wnts to RTK/MAPK signaling. Wnt inhibition drives increased recycling of RTKs and activation of the MAPK pathway, and this requires FAXDC2. Blocking Wnt signaling in Wnt-high cancers causes both differentiation and senescence; and this is prevented by knockout of FAXDC2. Our data shows the integration of three ancient pathways, Wnts, cholesterol synthesis, and RTK/MAPK signaling, in cellular proliferation and differentiation.
Babita Madan, Shawn R. Wadia, Siddhi Patnaik, Nathan Harmston, Emile K.W. Tan, Iain Bee Huat Tan, W. David Nes, Enrico Petretto, David M. Virshup
Given the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socio-economic challenge to the aging population, which is importantly attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with inflammatory hypersecretory phenotype due to aging and other damaged factors is a distinctive hallmark of IVDD initiation and progression. In this study, we revealed a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cGAS-STING axis but not AIM2 inflammasome assembly. ATR deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS-STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanically, the disassembly of ATR-TRIM56 complex with the enzyme activity liberation of USP5 and TRIM25 drove change in ATR ubiquitination, with ATR switching from K63-linked modification to K48-linked modification, promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescent progression. Importantly, an engineered extracellular vesicle (EV)-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and efficient approaches for ameliorating the impact of IVDD.
Weifeng Zhang, Gaocai Li, Xingyu Zhou, Huaizhen Liang, Bide Tong, Di Wu, Kevin Yang, Yu Song, Bingjin Wang, Zhiwei Liao, Liang Ma, Wencan Ke, Xiaoguang Zhang, Jie Lei, Chunchi Lei, Xiaobo Feng, Kun Wang, Kangcheng Zhao, Cao Yang
Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity, dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.
Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang
Kristin Gabor, Emily V. Mesev, Jennifer Madenspacher, Julie M. Meacham, Prashant Rai, Sookjin Moon, Christopher A. Wassif, Saame Raza Shaikh, Charles J. Tucker, Peer W. Karmaus, Simona Bianconi, Forbes D. Porter, Michael B. Fessler
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