Pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death and is largely resistant to immunotherapies. The tumor microenvironment, largely composed of heterogeneous myeloid cells, creates a physical, metabolic, and immunosuppressive barrier that prevents T cells from infiltrating cancer beds. In this issue of the JCI, Markosyan and colleagues have reported a tumor-intrinsic mechanism that excludes T cells from the vicinity of tumor cells. They showed that a receptor tyrosine kinase, ephrin-A receptor 2 (EPHA2), regulates prostaglandin endoperoxide synthase 2 (PTGS2) (encodes COX-2) expression in a TGF-β signaling–dependent manner. Genetic ablation of Epha2 or Ptgs2 in preclinical models or pharmacological inhibition of COX-2 elicited the transformation of this immunosuppressive microenvironment into a T cell–permissive milieu. Consequent T cell relocation rendered this immunoresistant malignancy responsive to combinations of checkpoint blockers and CD40 agonists. Because the association between T cell infiltration and the EPHA2/TGF-β/COX-2 axis is supported by independent clinical data, these results provide a rationale for ensuing clinical trials aimed at incorporating pancreatic cancer into the range of immunotherapy-responsive tumors.
Jose R. Conejo-Garcia
The oxygen-sensing prolyl hydroxylase domain (PHD) enzymes are key to maintaining tissue homeostasis during hypoxia via their regulation of the expression and activity of HIF, the master transcription factor for the hypoxic response. In this issue of the JCI, Yamamoto, Hester, and colleagues show that temporal and reversible inhibition of PHD2 in vivo leads to systemic autoimmune disorder. The work demonstrates that a reduction of PHD2 leads to impairment of immunosuppressive Treg cell function via a HIF2α-dependent mechanism, without altering Foxp3 expression. This study indicates that a PHD2/HIF2α axis is critical for maintaining proper Treg function.
Weiping Zou, Yatrik M. Shah
Organ transplantation is now a preferred treatment for end-stage organ failure. Among the challenges for ensuring excellent clinical outcomes for transplant recipients is good initial allograft function at the time of organ implantation. This is determined in part by the functional status of the donor and donor organ, functional status of the recipient, and conduct of the operative procedure. Despite optimization of these variables, organ transplantation is still often plagued by substantial initial dysfunction, variably referred to as slow or delayed graft function, or in the most extreme cases, primary graft nonfunction necessitating urgent regrafting. In this issue of the JCI, Nakamura, Kageyama, Ito, Hirao, and colleagues investigate a potential role for the recipient’s microbiome in determining graft function after liver transplantation and demonstrate the benefits of antibiotic pretreatment in both a mouse model and in human patients.
Jonathan S. Bromberg, Joseph R. Scalea, Emmanuel F. Mongodin
Neurologic involvement of HIV remains an important concern for patients, physicians, and investigators. Catastrophic decline is rarely seen in patients on combination antiretroviral therapy (cART); however, neurological decline remains a critical clinical challenge. In this issue of the JCI, Spudich and associates investigated the status of HIV in the cerebral spinal fluid (CSF) and revealed ongoing presence of HIV in the nervous system. Surprisingly, even in the face of optimal treatment, including suppressed HIV RNA, almost half of the patients investigated showed cell-associated HIV (CA-HIV) DNA in the CSF. Spudich et al. find that persistence of HIV in CSF cells is associated with lower performance on neurocognitive testing. These findings emphasize the need to consider a viral-associated mechanism as playing a significant and potentially ongoing role in HIV-associated neurocognitive disorder (HAND).
David B. Clifford
The discovery of insulin almost 100 years ago has resulted in a remarkable increase in lifespan and quality of life for patients with type 1 diabetes. The Joslin Medalist Study has allowed researchers to access and study patients (Medalists) with type 1 diabetes who have been insulin dependent for 50 years or more. In this issue of the JCI, Yu et al. evaluated HLA variants, autoantibody status, β cell function, C-peptide release, and monogenetic diabetes genes in a cohort of Medalists. Postmortem analysis of pancreata from Medalists revealed the presence of insulin-positive β cells in these patients. Moreover, some patients were still able to respond to metabolic stimuli despite long-term insulin dependence. Overall, the Medalist cohort was highly heterogenous, and genetic testing suggested that several patients would fall into categories other than type 1 diabetes on the basis of REVEL (rare exome variant ensemble learner) classification and may be able to transfer to other therapy options.
Fabrizio Barbetti, Simeon I. Taylor
T follicular helper (Tfh) cells in germinal centers of secondary lymphoid organs are pivotal for B and T cell interactions required for induction of humoral immunity. It has long been debated whether Tfh cells exit from lymph nodes into the blood as circulating Tfh cells. In this issue of the JCI, Vella et al. have taken the bull by the horns and applied considerable technical muscle to answer this question. By analyzing phenotype, transcriptome, epigenetic profile, and T cell receptor clonotype, the authors provide evidence that a subset of cTfh cells do indeed originate in lymph nodes and traffic into the blood via the thoracic duct.
Solid organ transplantation from hepatitis C virus–positive (HCV-positive) deceased donors into HCV-negative recipients is a recent approach aimed to expand the donor organ pool in the setting of severe shortage. Good short-term outcomes have been reported with this approach in combination with direct-acting antivirals. In this issue of the JCI, Zahid and colleagues have characterized early viral kinetics and the genetic landscape of donor-to-recipient HCV transmission using single-genome sequencing. In seven HCV-negative recipients of four HCV-positive donor organs, productive infection with a highly diverse viral population was seen by day three after transplantation. The degree of genetic diversity seen in recipients of HCV-positive organs was unlike the narrow genetic bottleneck typically observed with acute HCV acquisition from intravenous drug use or sexual activity. All recipients achieved HCV cure with treatment. The consequences of acute infection with a genetically diverse HCV population are unknown; however, early clinical experience with this transplantation strategy is promising.
Christine M. Durand, Michael A. Chattergoon
Lactation is a unique period in which the maternal skeleton acts as a storehouse to provide substantial calcium to milk. Women who exclusively breastfeed lose an average of 210 mg of calcium per day, which doubles or triples with twins and triplets. Data from rodent and clinical studies are consistent with skeletal calcium being released to provide much of the calcium needed for milk production. This is programmed to occur independently of dietary calcium intake or intestinal calcium absorption, which remains at the prepregnant rate in breastfeeding women. After weaning, the skeleton is restored to its prior mineralization and strength, but the factors that regulate this remain to be elucidated.
Brittany A. Ryan, Christopher S. Kovacs
Multiple myeloma (MM) is a relatively common hematologic malignancy, and up to half of patients with MM present with renal dysfunction at the time of diagnosis. MM-associated renal injury has been linked to an excess level of monoclonal immunoglobulin free light chains (FLCs) in the circulation; however, it is not clear how these FLCs drive renal pathology. In this issue of the JCI, Ying et al. unravel a novel mechanism by which FLCs mediate renal injury in MM by inducing fibrotic and inflammatory pathways in the kidney. Specifically, FLC-mediated production of H2O2 was shown to activate JAK2/STAT1 signaling, increase production of IL-1β via induction of capsase-1, and promote activation of TGF-β via αvβ6 integrin. Moreover, the authors identified a tryptophan residue within a specific monoclonal FLC that was required for optimal H2O2 production and downstream signaling. A better understanding of the drivers of MM-associated renal injury has potential for the identification of promising therapeutic targets.
Erin B. Taylor, Michael J. Ryan
In this issue of the JCI, Panigrahy et al. demonstrate that preoperative administration of the antiinflammatory drug ketorolac or specialized proresolving mediators (SPM) called resolvins increases disease-free survival rates and prevents metastasis after surgery and chemotherapy in mouse models of cancer. The antitumor response was partially mediated by tumor-specific T cell immunity and immunological memory.
Esra Güç, Jeffrey W. Pollard
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