Commentaries
Abstract
Killer immunoglobulin-like receptors (KIRs) are polymorphic receptors for human leukocyte antigens (HLAs) that provide positive or negative signals controlling lymphocyte activation. Expression of inhibitory KIRs by CD8+ T cells affects their survival and function, which is linked to improved antiviral immunity and prevention of autoimmunity. In this issue of the JCI, Zhang, Yan, and co-authors demonstrate that increased numbers of functional inhibitory KIR-HLA pairs equating to greater negative regulation promoted longer lifespans of human T cells. This effect was independent of direct signals provided to KIR-expressing T cells and was instead driven by indirect mechanisms. Since the long-term maintenance of CD8+ T cells is critical for immune readiness against cancer and infection, this discovery has implications for immunotherapy and the preservation of immune function during aging.
Authors
H. Alex Feldman, Hilal Cevik, Stephen N. Waggoner
Abstract
Type I IFNs, a family of cytokines that signal through a single receptor and signaling mechanism, were originally named for their ability to interfere with viral replication. While type II IFN (IFN-γ) largely protects against intracellular bacteria and protozoa, type I IFNs largely protect from viral infections. Inborn errors of immunity in humans have demonstrated this point and its clinical relevance with increasing clarity. In this issue of the JCI, Bucciol, Moens, et al. report the largest series of patients to date with deficiency of STAT2, an important protein for type I IFN signaling. Individuals with STAT2 loss demonstrated a clinical phenotype of viral susceptibility and inflammatory complications, many of which remain poorly understood. These findings further illustrate the very specific and critical role that type I IFNs play in host defense against viruses.
Authors
Michael B. Jordan
Abstract
Palmitoylation is a critical posttranslational modification that enables the cellular membrane localization and subsequent activation of RAS proteins, including HRAS, KRAS, and NRAS. However, the molecular mechanism that regulates RAS palmitoylation in malignant diseases remains unclear. In this issue of the JCI, Ren, Xing, and authors shed light on this topic and revealed how upregulation of RAB27B, as a consequence of CBL loss and Janus kinase 2 (JAK2) activation, contributes to leukemogenesis. The authors found that RAB27B mediated NRAS palmitoylation and plasma membrane localization by recruiting ZDHHC9. The findings suggest that targeting RAB27B could provide a promising therapeutic strategy for NRAS-driven cancers.
Authors
Fang Yu, Zhijian Qian
Abstract
Fumarate hydratase–deficient (FH-deficient) renal cell carcinoma (RCC) represents a particularly aggressive form of kidney cancer. FH-deficient RCC arises in the setting of germline, or solely somatic, mutations in the FH gene, a two-hit tumor suppressor gene. Early detection can be curative, but there are no biomarkers, and in the sporadic setting, establishing a diagnosis of FH-deficient RCC is challenging. In this issue of the JCI, Zheng, Zhu, and co-authors report untargeted plasma metabolomic analyses to identify putative biomarkers. They discovered two plasma metabolites directly linked to fumarate overproduction by tumor cells, succinyl-adenosine and succinic-cysteine, which correlate with tumor burden. The identification of circulating biomarkers of FH-deficient RCC may aid in the diagnosis of FH-deficient RCC and provide a means for longitudinal follow-up.
Authors
Divya Bezwada, James Brugarolas
Abstract
The cytokine IL-6 has well-known proinflammatory roles in aging and ischemic heart disease. In this issue of the JCI, Alter and colleagues used mouse experiments and human tissue to investigate the source of IL-6 following myocardial infarction. The authors showed that cardiac fibroblasts produced IL-6 after coronary ligation in mice and proposed the existence of a pathway involving adenosine signaling via the adenosine A2b receptor. The findings underscore the complexity of IL-6 biology in ischemic heart disease and identify an adenosine/IL-6 pathway that warrants consideration for targeting as a modulator of cardiovascular risk.
Authors
Tetsushi Nakao, Peter Libby
Abstract
Deficiencies in homologous recombination (HR) repair lead to an accumulation of DNA damage and can predispose individuals to cancer. Polymerase theta (Pol θ, encoded by POLQ) is overexpressed by HR-deficient cancers and promotes cancer cell survival by mediating error-prone double-stranded break (DSB) repair and facilitating resistance against poly-ADP ribose polymerase inhibitor treatment. In this issue of the JCI, Oh, Wang, et al. report on the impact of Pol θ inhibition on activation of antitumor immunity. The authors used pancreatic ductal adenocarcinoma (PDAC) cell and mouse models characterized by HR-associated gene alterations and POLQ overexpression. POLQ knockdown showed synthetic lethality in combination with gene mutations involving DNA repair, including BRCA1, BRCA2, and ATM. Notably, Pol θ deficiency or inhibition suppressed tumor growth, increased the accumulation of unrepaired DNA damage, and enhanced T cell infiltration via the cGAS/STING pathway. These findings suggest a broader scope for Pol θ inhibition in HR-deficient cancers.
Authors
Chelsea M. Smith, Gaorav P. Gupta
Abstract
Endothelial cells form a constitutively anticoagulant surface under homeostasis. While loss of this anticoagulant property is a hallmark of many cardiovascular diseases, the molecular mechanisms underlying the procoagulant transition remain incompletely understood. In this issue of the JCI, Schmaier et al. identify the phospholipid scramblases TMEM16E and TMEM16F, which support endothelial procoagulant activity through phosphatidylserine (PS) externalization. Genetic deletion of TMEM16E or TMEM16F or treatment with TMEM16 inhibitors prevented PS externalization and reduced fibrin formation in the vessel wall independently of platelets in a murine laser-injury model of thrombosis. These findings reveal a role for endothelial TMEM16E in thrombosis and identify TMEM16E as a potential therapeutic target for preventing thrombus formation.
Authors
János G. Filep
Abstract
Spastic paraplegia 50 (SPG50) is a rare neurodegenerative disease caused by loss-of-function mutations in AP4M1. There are no effective treatments for SPG50 or any other type of SPG, and current treatments are limited to symptomatic management. In this issue of the JCI, Chen et al. provide promising data from preclinical studies that evaluated the efficacy and safety profiles of an AAV-mediated AP4M1 gene replacement therapy for SPG50. AAV/AP4M1 gene replacement partly rescued functional defects in SPG50 cellular and mouse models, with acceptable safety profiles in rodents and monkeys. This work represents a substantial advancement in therapeutic development of SPG50 treatments, establishing the criteria for taking AAV9/AP4M1 gene therapy to clinical trials.
Authors
Jonathan R. Brent, Han-Xiang Deng
Abstract
Cytomegalovirus (CMV) viremia from reactivation of latent infection is a common complication after allogeneic hematopoietic cell transplantation (HCT). Untreated, CMV viremia can progress to affect other organs, resulting in organ dysfunction with high morbidity and mortality. In this issue of the JCI, Prockop and authors demonstrate that third-party donor T cells sensitized ex vivo to CMV pp65-derived overlapping pentadecapeptides are safe and effective for the treatment of CMV reactivation or CMV disease refractory to first-line pharmacotherapies occurring after HCT. They also provide insight into the biological differences between responders and nonresponders. This work confirms the utility of third-party CMV pp65 VSTs and suggests strategies for further improving the efficacy of this cell-therapy approach.
Authors
George L. Chen, Elizabeth J. Shpall
Abstract
Treatment-resistant cancer, such as neuroendocrine prostate cancer (NEPC), is a lethal disease with limited therapeutic options. RB1 is a tumor suppressor gene that is lost in a majority of NEPC tumors. In this issue of the JCI, Wang and colleagues examined how RB1 loss may sensitize cancer cells to ferroptosis inducers through elevation of ACSL4, a key enzyme that promotes lipid peroxidation and triggers ferroptosis. We discuss a high potential of RB1-deficient cells to undergo ferroptosis due to the elevation of ACSL4. This is normally kept in check by abundant expression of GPX4, an antioxidant enzyme, in cancer cells. This balance, however, is tilted by GPX4 inhibitors, leading to massive ferroptosis. We highlight possible therapeutic strategies that exploit this inherent vulnerability for targeting RB1-deficient, treatment-resistant cancer.
Authors
Wanqing Xie, Shivani Agarwal, Jindan Yu
No posts were found with this tag.
Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)