CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis
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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”).
Targeting Pancreatic Cancer Metabolic Dependencies Through Glutamine Antagonism
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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.
Simian Immunodeficiency Virus and Storage Buffer: Field-Friendly Preservation Methods for RNA Viral Detection in Primate Feces
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Simian immunodeficiency virus (SIV) infects more than 40 nonhuman primate (NHP) species in sub-Saharan Africa, but testing in wild NHP populations can be challenging. Researchers compared methods for SIV RNA preservation and recovery from NHP fecal samples stored in four different buffers. The goal of this work was to identify a robust “field-friendly” method (i.e., without freezing or refrigeration) for this effort, and the samples were collected from a mantled guereza colobus housed at the Columbus Zoo and Aquarium.
Lymphoid Tissues Contribute to Plasma Viral Clonotypes Early After Antiretroviral Therapy Interruption in SIV-Infected Rhesus Macaques
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Researchers are interested in better understanding the sources, timing, and mechanisms of HIV rebound that occurs after interruption of antiretroviral therapy (ART). Using rhesus macaques (sex not specified), investigators tracked barcoded simian immunodeficiency virus (SIV) clonotypes over time and among tissues. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. Additionally, the authors reported that CD4+ T cells harbored the most viral RNA after ART interruption.
Antiretroviral Therapy Reveals Triphasic Decay of Intact SIV Genomes and Persistence of Ancestral Variants
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Antiretroviral therapy (ART) halts HIV-1 replication but is not curative; a pool of latently infected CD4+ T cells persists, and viremia rapidly rebounds if ART is stopped. Using an intact proviral DNA assay, researchers characterized quantitative and qualitative changes in CD4+ T cells for 4 years following ART initiation in rhesus macaques of both sexes. They found that viruses replicating at ART initiation had mutations conferring antibody escape, and sequences with large numbers of antibody escape mutations became less abundant at later time points.
The Immune Landscape in Tuberculosis Reveals Populations Linked to Disease and Latency
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Mycobacterium tuberculosis infection of adult rhesus macaques (RMs), predominantly males (81%), recapitulates both latent (LTBI) and active pulmonary TB (PTB) observed in humans. The immune characterization in lungs of RMs with PTB exhibited an influx of plasmacytoid dendritic cells, an interferon-responsive macrophage population, and activated T cell responses. In contrast, a CD27+ natural killer (NK) cell subset accumulated in the lungs of RMs with LTBI. This NK cell population was also detected in the circulation of humans with LTBI.
Lipocalin-2 Is an Anorexigenic Signal in Primates
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The hormone lipocalin-2 (LCN2) suppresses food intake in mice. Researchers demonstrated that LCN2 increases after a meal and reduces hunger in people with normal weight or overweight, but not in obese individuals. The researchers also showed that LCN2 crosses the blood-brain barrier and binds to the hypothalamus in vervet monkeys. LCN2 was found to bind to the hypothalamus in human, baboon, and rhesus macaque brain sections. When injected into vervets, LCN2 suppressed food intake and lowered body weight without toxic effects in short-term experiments.
Antiretroviral Therapy Does Not Reduce Tuberculosis Reactivation in a Tuberculosis-HIV Coinfection Model
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Despite treatment of HIV with antiretroviral therapy (ART), the risk of tuberculosis (TB) reactivation is higher in HIV-infected than HIV-uninfected persons. Researchers used Mycobacterium tuberculosis/SIV-coinfected rhesus macaques to model the impact of ART on TB reactivation due to HIV-induced immunosuppression. ART significantly reduced viral loads and increased CD4+ T-cell counts in blood, spleen, and bronchoalveolar lavage samples, but it did not reduce the risk of SIV-induced TB reactivation during the early phase of treatment.
Induction and Characterization of Pancreatic Cancer in a Transgenic Pig Model
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Preclinical testing of new therapies for pancreatic cancer has been challenging due to lack of a suitable large animal model. Pigs, however, have similar physiology and immune response to humans. Boas et al report the development of a porcine model for pancreatic cancer. H&E and immunohistochemical stains revealed undifferentiated carcinomas, like those of human pancreatobiliary systems. In several pigs, angiographies revealed that the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter.
HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
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New patterns of gene expression are enacted and regulated during tissue regeneration. Romidepsin, an FDA-approved HDAC inhibitor, potently blocks axolotl embryo tail regeneration by altering initial transcriptional responses to injury. Regeneration inhibitory concentrations of romidepsin increased and decreased the expression of key genes. Single-nuclei RNA sequencing at 6 HPA illustrated that key genes were altered by romidepsin in the same direction across multiple cell types.