Desai et al. report that the tumor microenvironment of lung cancers from people with HIV exhibits a more immunoregulatory environment compared with that in people without HIV. The cover image shows HIV-positive non-small cell lung cancer with immune cell infiltration, stained by imaging mass cytometry.
Birth defects are the leading cause of infant mortality, and most inborn errors of development are multifactorial in origin, resulting from complex gene-environment interactions. Defining specific gene-environment interactions in the etiology and pathogenesis of congenital disorders is critically needed in the absence of genotype-phenotype correlation but is challenging. This is particularly true for congenital craniofacial anomalies, which account for approximately one-third of all birth defects, as they typically exhibit considerable inter-familial and intra-familial variability. A classic example of this is Treacher Collins Syndrome (TCS), which, although primarily caused by mutations in TCOF1, is characterized by considerable variability in the severity of mandibulofacial dysostosis. Here, we describe the genetic and environmental factors with converging effects that mechanistically contribute to the etiology and pathogenesis of craniofacial variation in this rare congenital disorder. We discovered in Tcof1+/- mouse models of TCS, that the combination of different endogenous levels of Tcof1/Treacle protein and reactive oxygen species (ROS) within distinct genetic backgrounds correlates with TCS phenotype severity. Furthermore, geometric morphometric analyses revealed that genotype largely determines the craniofacial shape, but redox status determines the size of individual bones. Taken together, our results highlight the roles of ROS and genomic instability in modulating the variability and phenotypic severity of craniofacial anomalies.
Sharien Fitriasari, Roberta Fiorino, Thoa H.K. Truong, Mary C. McKinney, Jill Dixon, Michael J. Dixon, Paul A. Trainor
Inactivation of cyclin-dependent kinase 12 (CDK12) defines an immunogenic molecular subtype of prostate cancer characterized by genomic instability and increased intratumoral T cell infiltration. This study reveals that genetic or pharmacologic inactivation of CDK12 and its paralog CDK13 robustly activates stimulator of interferon genes (STING) signaling across multiple cancer types. Clinical cohort analysis shows that reduced CDK12/13 expression correlates with improved survival and response to immune checkpoint blockade (ICB). Mechanistically, CDK12/13 depletion or targeted degradation induces cytosolic nucleic acid release, triggering STING pathway activation. CDK12/13 degradation delays tumor growth and synergizes with anti-PD1 therapy in syngeneic tumor models, enhancing STING activity and promoting CD8+ T cell infiltration and activation within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings establish STING activation as the key driver of T cell infiltration and the immune-hot tumor microenvironment in CDK12 mutant cancers, suggesting that dual CDK12/13 inhibitors and degraders activate anti-tumor immunity and potentiate responses to immunotherapies.
Yi Bao, Yu Chang, Jean Tien, Gabriel Cruz, Fan Yang, Rahul Mannan, Somnath Mahapatra, Radha Paturu, Xuhong Cao, Fengyun Su, Rui Wang, Yuping Zhang, Mahnoor Gondal, Jae Eun Choi, Jonathan K. Gurkan, Stephanie J. Miner, Dan R. Robinson, Yi-Mi Wu, Licheng Zhou, Zhen Wang, Ilona Kryczek, Xiaoju Wang, Marcin Cieslik, Yuanyuan Qiao, Alexander Tsodikov, Weiping Zou, Ke Ding, Arul M. Chinnaiyan
The cystine-xCT transporter–glutathione (GSH)–GPX4 axis is the canonical pathway protecting cells from ferroptosis. While GPX4-targeting ferroptosis-inducing compounds (FINs) act independently of mitochondria, xCT-targeting FINs require mitochondrial lipid peroxidation, though the mechanism remains unclear. Since cysteine is also a precursor for coenzyme A (CoA) biosynthesis, here, we demonstrated that CoA supplementation selectively prevented ferroptosis triggered by xCT inhibition by regulating the mitochondrial thioredoxin system. Our data showed that CoA regulated the in vitro enzymatic activity of mitochondrial thioredoxin reductase (TXNRD2) by covalently modifying the thiol group of cysteine (CoAlation) on Cys-483. Replacing Cys-483 with alanine on TXNRD2 abolished its enzymatic activity and ability to protect cells against ferroptosis. Targeting xCT to limit cysteine import and, therefore, CoA biosynthesis reduced CoAlation on TXNRD2. Furthermore, the fibroblasts from patients with disrupted CoA metabolism demonstrated increased mitochondrial lipid peroxidation. In organotypic brain slice cultures, inhibition of CoA biosynthesis led to an oxidized thioredoxin system, increased mitochondrial lipid peroxidation, and loss of cell viability, which were all rescued by ferrostatin-1. These findings identified CoA-mediated post-translational modification to regulate the thioredoxin system as an alternative ferroptosis protection pathway with potential clinical relevance for patients with disrupted CoA metabolism.
Chao-Chieh Lin, Yi-Tzu Lin, Ssu-Yu Chen, Yasaman Setayeshpour, Yubin Chen, Denise E. Dunn, Taylor Nguyen, Alexander A. Mestre, Adrija Banerjee, Lalitha Guruprasad, Erik J. Soderblom, Guo-Fang Zhang, Chen-Yong Lin, Valeriy Filonenko, Suh Young Jeong, Scott R. Floyd, Susan J. Hayflick, Ivan Gout, Jen-Tsan Chi
Pathogenic variants in the gene TMPRSS3 are a common cause of hearing loss in humans, although the causal mechanisms remain unknown. Previous work has shown that Tmprss3Y260X/Y260X mice exhibit normal hair cell development, mechanosensory transduction, and spiral ganglion patterning, but experience rapid hair cell death from P12 to P14 at the onset of hearing. Here, we demonstrate that Tmprss3Y260X/Y260X mice display an early and temporary spike in endocochlear potential (EP) prior to the onset of hair cell death. In vitro experiments with cochlear explants from Tmprss3Y260X/Y260X mice and in vivo studies with Tmprss3Y260X/Y260X mice crossed with two different mutant models that lacked EP generation promoted hair cell survival. Furthermore, systemic administration of furosemide, a drug that reduces EP in vivo, reduced hair cell death in Tmprss3Y260X/Y260X mice. These findings suggest that extracellular factors, including EP, play a role in TMPRSS3-related hair cell survival and hearing loss, and suggest that modulating EP could be a therapeutic strategy.
A. Eliot Shearer, Yuan-Siao Chen, Stephanie L. Rouse, Xiaohan Wang, Janmaris Marin Fermin, Kevin T.A. Booth, Jasmine Moawad, Nicole Bianca Libiran, Jinan Li, Hae-Young Kim, Michael Hoa, Rafal Olszewski, Jing-Yu Lei, Ernesto Cabrera, Douglas J. Totten, Bo Zhao, Jeffrey R. Holt, Rick F. Nelson
Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.
Jheng-Syuan Shao, Alan C. Lai, Wei-Chang Huang, Ko-Chien Wu, Po-Yu Chi, Yao-Ming Chang, Ya-Jen Chang