Selected Grantee Publications
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- 11 results found
- niaid
- Cancer
- Stem Cells/Regenerative Medicine
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
Evolution of the Clinical-Stage Hyperactive TcBuster Transposase as a Platform for Robust Non-Viral Production of Adoptive Cellular Therapies
Skeate et al., Molecular Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38627969/
In this study, the authors report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure-guided and in vitro evolution approaches that achieve high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. This proof-of-principle TcB-M engineering of CAR-NK and CAR-T cells shows low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improved survival in a Burkitt lymphoma xenograft model in vivo. Their work suggests that TcB-M is a versatile, safe, efficient, and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition. Supported by ORIP (F30OD030021), NCI, NHLBI, and NIAID.
CD8+ T Cell Targeting of Tumor Antigens Presented by HLA-E
Iyer, Science Advances. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086602/
Researchers have hypothesized that human leukocyte antigen-E (HLA-E)–positive cancer cells could be targeted by HLA-E–restricted CD8+ T cells. In this study, the authors assessed whether major histocompatibility complex E (MHC-E) expression by cancer cells can be targeted for MHC-E–restricted T cell control. Using male rhesus macaques, they found that a cytomegalovirus can be used as a vector to generate specific immune cells that can target cancer cells. The authors conclude that targeting HLA-E with restricted, specific CD8+ T cells could offer a new approach for immunotherapy of prostate cancer. Overall, this study supports the concept of a cancer vaccine. Supported by ORIP (P51OD011092) and NIAID.
CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
Nayyer et al., Clinical Cancer Research. 2024.
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. In this study, investigators evaluated the efficacy of combining CDKi (abemaciclib) and anti–PD-1 therapy (“combination therapy”) in mouse models for brain metastases, elucidated how combination therapy remodeled the tumor–immune microenvironment (TIME) and T-cell receptor (TCR) repertoires, and investigated the effects of CDKi on T-cell development and maintenance in NOD-scid Il2rgnull (NSG) mice engrafted with human immune systems (“humanized mice”). Results offer a strong rationale for the clinical evaluation of combination CDKi and PD-1 blockade in patients with brain metastases. Supported by ORIP (R24OD026440), NCI, and NIAID.
Targeting Pancreatic Cancer Metabolic Dependencies Through Glutamine Antagonism
Encarnación-Rosado et al., Nature Cancer. 2024.
https://pubmed.ncbi.nlm.nih.gov/37814010/
Pancreatic ductal adenocarcinoma (PDAC) cells thrive in the austere, complex tumor microenvironment by reprogramming their metabolism and relying on scavenging pathways, but more work is needed to translate this knowledge into clinically relevant therapeutic interventions. Investigators demonstrated that treating PDAC cells with a Gln antagonist, 6‑diazo-5-oxo-l-norleucine (DON), caused a metabolic crisis by globally impairing Gln metabolism, resulting in a significant decrease in proliferation. They observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. Combining this therapeutic with an extracellular-signal-regulated kinase (or ERK) signaling pathway inhibitor could further improve it. Supported by ORIP (S10OD021747), NCI, and NIAID.
Allogeneic Immunity Clears Latent Virus Following Allogeneic Stem Cell Transplantation in SIV-Infected ART-Suppressed Macaques
Wu et al., Immunity. 2023.
https://doi.org/10.1016/j.immuni.2023.04.019
Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been documented as curative for HIV, but the mechanisms are not yet known. Using Mauritian cynomolgus macaques of both sexes, researchers performed reduced-intensity alloHSCT experiments to define the individual contributions of allogeneic immunity and CCR5 deficiency to an alloHSCT-mediated HIV cure. They reported that allogeneic immunity was the major driver of reservoir clearance, mediating graft-versus-reservoir effects in HIV infection. Their results also point to a protective mechanism for CCR5 deficiency early during engraftment. Future efforts could focus on harnessing the beneficial effects of allogeneic immunity while avoiding graft-versus-host disease. Supported by ORIP (P51OD011092) and NIAID.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
In-Depth Virological and Immunological Characterization of HIV-1 Cure after CCR5A32/A32 Allogeneic Hematopoietic Stem Cell Transplantation
Jensen et al., Nature Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/36807684/
Evidence suggests that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure HIV-1, but the immunological and virological correlates are unknown. Investigators performed a longitudinal virological and immunological analysis of the peripheral blood and tissue compartments of a 53-year-old male patient more than 9 years after CCR5Δ32/Δ32 allogeneic HSCT and 48 months after analytical treatment interruption. Sporadic traces of HIV-1 DNA were detected in peripheral T cell subsets and tissue-derived samples, but repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice of both sexes did not reveal replication-competent virus. This case provides new insights that could guide future cure strategies. Supported by ORIP (P51OD011092) and NIAID.
Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
Abeynaike et al., Viruses. 2023.
https://www.mdpi.com/1999-4915/15/2/365
A major obstacle to human natural killer (NK) cell reconstitution is the lack of human interleukin‑15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Researchers show that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical cord blood–derived hematopoietic stem cells (HSCs). These mice demonstrate robust and long-term reconstitution with human immune cells but do not develop graft-versus-host disease, allowing long-term studies of human NK cells. The HSC-engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses. This work provides a robust novel model to study NK cell responses to HIV-1. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.