Publications by authors named "Jennifer A Foltz"

Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells.

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  • CD8α is a receptor found on a variable percentage of human NK cells, and its role in NK cell function is not well understood, especially in the context of leukemia treatment.
  • Studies showed that CD8α- NK cells effectively controlled leukemia in models, likely due to better proliferation, whereas CD8α+ NK cells were associated with poorer therapeutic outcomes.
  • IL-15 stimulation led to the induction of CD8α on previously CD8α- NK cells, enhancing their proliferation and activity, with CD8A deletion showing potential to boost NK cell activity by affecting the balance of activating and inhibitory receptors.
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Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies.

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Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients.

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  • The study utilizes ultra-deep exome sequencing to analyze the scarce malignant Hodgkin and Reed Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL), enabling better detection of somatic mutations compared to traditional methods.* -
  • Researchers identified novel mutations in several genes and recurrent patterns affecting pathways related to Hippo signaling, thereby expanding the understanding of genetic factors involved in cHL.* -
  • Additionally, single-nuclei RNA sequencing confirmed the presence of somatic mutations in specific cell clusters, providing insight into the malignant characteristics of HRS cells and establishing a methodology for future genomic studies in larger cHL patient cohorts.*
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  • Head and neck squamous cell carcinoma (HNSCC) is challenging to treat, especially with PD-1 blockade therapy, prompting researchers to explore enhancing natural killer (NK) cell therapies.
  • The study generated memory-like (ML) NK and conventional (c)NK cells, assessing their effectiveness in attacking HNSCC cells, particularly when combined with cetuximab or engineered with an anti-EphA2 CAR.
  • Results showed that ML NK cells were significantly more effective at killing HNSCC cells and that their performance improved further with cetuximab, supporting the potential of these combined therapies in clinical trials.
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Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells.

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  • The accumulation of senescent cells (SNCs) contributes to chronic inflammation and age-related diseases, but the bifunctional immunotherapeutic HCW9218 can reduce these cells and their harmful effects.
  • In diabetic mice, HCW9218 improved glucose metabolism and insulin resistance by decreasing senescent pancreatic beta cells and related inflammation.
  • Additionally, in aged mice, HCW9218 not only lowered senescent cells but also improved gene expression linked to metabolism and longevity, enhancing physical performance without harming their overall health.
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Lyme disease (LD) due to Borrelia burgdorferi is the most prevalent vector-borne disease in the United States. There is a poor understanding of how immunity contributes to bacterial control, pathology, or both during LD. Dogs in an area of endemicity were screened for B.

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Natural killer (NK) cells are cytotoxic innate lymphoid cells that are emerging as a cellular immunotherapy for various malignancies. NK cells are particularly dependent on interleukin (IL)-15 for their survival, proliferation, and cytotoxic function. NK cells differentiate into memory-like cells with enhanced effector function after a brief activation with IL-12, IL-15, and IL-18.

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Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18.

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  • Pediatric and young adult patients with relapsed acute myeloid leukemia (AML) after stem cell transplant usually have a very poor outlook, and current treatments like standard chemotherapy and donor lymphocyte infusions are not very effective.
  • A phase 1 trial treated 9 patients with memory-like natural killer (ML NK) cells that were generated from their original stem cell donors, showing promising results with 4 out of 8 evaluable patients achieving complete remission after two weeks.
  • The study found that these ML NK cells can expand and persist in the body with strong anti-leukemia responses, indicating they could be an effective new immunotherapy option for relapsed AML without significant toxicity.
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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular processes in cancer and immunity, including innate immune cell development and effector function. However, the transcriptional repertoire through which AHR mediates these effects remains largely unexplored. To elucidate the transcriptional elements directly regulated by AHR in natural killer (NK) cells, we performed RNA and chromatin immunoprecipitation sequencing on NK cells exposed to AHR agonist or antagonist.

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Purpose: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses.

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Purpose: N-803 is an IL15 receptor superagonist complex, designed to optimize persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8 T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.

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Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear.

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Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) that mediate antiviral and antitumor responses and require the transcriptional regulator Eomesodermin (Eomes) for early development. However, the role of Eomes and its molecular program in mature NK cell biology is unclear. To address this, we develop a tamoxifen-inducible, type-1-ILC-specific (Ncr1-targeted) cre mouse and combine this with Eomes-floxed mice.

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Background: Optimal expansion of therapeutic natural killer (NK) cell products has required media supplementation with human or fetal bovine serum, which raises safety and regulatory concerns for clinical manufacturing. Serum-free media (SFM) have been optimized for T-cell expansion, but few SFM systems have been developed for NK cells. Here, we compare six commercial clinical-grade SFM with our standard fetal bovine serum-containing medium for their ability to support NK cell expansion and function.

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We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression.

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Transforming growth factor-beta (TGFβ) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFβ. Herein, we sought to determine if TGFβ imprinting (TGFβi) during NK cell activation and expansion would decrease NK cell sensitivity to TGFβ suppression.

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Background: The mechanism by which natural killer (NK) cell education results in licensed NK cells with heightened effector function against missing self-targets is not known.

Objective: We sought to identify potential mechanisms of enhanced function in licensed human NK cells.

Methods: We used expanded human NK cells from killer immunoglobulin-like receptor (KIR)/HLA-genotyped donors sorted for single-KIR cells to generate pure populations of licensed and unlicensed NK cells.

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CRISPR/Cas9 technology is accelerating genome engineering in many cell types, but so far, gene delivery and stable gene modification have been challenging in primary NK cells. For example, transgene delivery using lentiviral or retroviral transduction resulted in a limited yield of genetically-engineered NK cells due to substantial procedure-associated NK cell apoptosis. We describe here a DNA-free method for genome editing of human primary and expanded NK cells using Cas9 ribonucleoprotein complexes (Cas9/RNPs).

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Background: We have previously shown that radiotherapy (RT) augments natural killer (NK) functions in pre-clinical models of human and mouse cancers, including sarcomas. Since dogs are an excellent outbred model for immunotherapy studies, we sought to assess RT plus local autologous NK transfer in canine sarcomas.

Methods: Dog NK cells (CD5, NKp46+) were isolated from PBMCs and expanded with irradiated K562-C9-mIL21 feeder cells and 100 IU/mL recombinant human IL-2.

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Canines spontaneously develop many cancers similar to humans - including osteosarcoma, leukemia, and lymphoma - offering the opportunity to study immune therapies in a genetically heterogeneous and immunocompetent environment. However, a lack of antibodies recognizing canine NK cell markers has resulted in suboptimal characterization and unknown purity of NK cell products, hindering the development of canine models of NK cell adoptive immunotherapy. To this end, we generated a novel antibody to canine NCR1 (NKp46), the putative species-wide marker of NK cells, enabling purification of NK cells for further characterization.

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