Selected Grantee Publications
- 666 results found
Gastrointestinal MAIT Cells in Chronic HIV-1 Infection
Ferre et al., Journal of Immunology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41024436
Mucosa-associated invariant T (MAIT) cells are innate-like T cells abundant in blood and the gastrointestinal tract. They help control infections by producing immunoproteins, killing infected cells, and hindering microbial growth. Chronic HIV infection reduces MAIT cells and increases vulnerability to secondary infections. In this work, researchers studied immunological responses of blood and mucosal MAIT cells to microbes between people (both sexes) with chronic HIV who are on long-term antiretroviral therapy and people without HIV. While MAIT cells were depleted in the blood of HIV-infected individuals, mucosal MAIT cell levels remained comparable between the two groups. Blood MAIT cells responded robustly to general immune stimulation. However, mucosal MAIT cells responded poorly to Escherichia coli bacterial stimulation, suggesting selective unresponsiveness to normal microbes while maintaining immune functions to other stimuli. HIV-infected individuals showed an impaired MAIT cell antimicrobial defense, providing novel insights worth studying. Supported by ORIP (S10OD018223), NCI, and NIDDK.
Targeting FSP1 Triggers Ferroptosis in Lung Cancer
Wu et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41193800
Growing evidence shows that cancer cells are highly sensitive to lipid peroxidation (a chemical process that degrades lipids in cell membranes). Ferroptosis is a form of cell death that relies on iron and lipid peroxidation, and two proteins known to suppress ferroptosis are GPX4 and FSP1. In this study, researchers used 8- to 12-week-old genetically engineered mouse models for lung cancer (both sexes used) and selectively deleted these two proteins. Results showed that deleting GPX4 and FSP1 triggered lipid peroxidation and significantly inhibited lung adenocarcinoma tumor development. FSP1 was essential for protecting tumors from ferroptosis in vivo (within an organism) but not in vitro (outside of an organism), highlighting the utility of the mouse models to mimic the physiological conditions of patients. FSP1 expression correlated with disease progression and reduced survival in lung adenocarcinoma patients (sex not stated), unlike GPX4. Drug inhibition of FSP1 showed substantial therapeutic efficacy in preclinical models. These findings establish ferroptosis as a barrier to tumor development and identify FSP1 inhibition as a promising novel therapy for lung cancer patients. Supported by ORIP (S10OD021747, S10OD032292), NCI, and NIGMS.
NSD2 Targeting Reverses Plasticity and Drug Resistance in Prostate Cancer
Li et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41299174
Most prostate cancer tumors develop resistance to therapies. In castration-resistant prostate cancer (CRPC), lineage plasticity—a cancer cell’s ability to change physical characteristics and behavior—drives disease progression and promotes drug resistance. NSD2 is a protein involved in modifying histones to change gene expression. NSD2 upregulation in neuroendocrine prostate cancer correlates with poor survival and regulates the genes that drive neuroendocrine differentiation. Using both mouse and human patient–derived organoids and 3- to 5-month-old NPp53 mice (sex not stated), researchers successfully reversed treatment resistance in neuroendocrine CRPC by inhibiting NSD2. Notably, combining NSD2 inhibition with enzalutamide (a current drug used to treat prostate cancer) effectively suppressed tumor growth and promoted cell death in multiple CRPC subtypes. These findings establish combination therapy as a promising therapeutic strategy for lethal forms of CRPC that are currently treatment resistant. Supported by ORIP (S10OD021764, S10OD012351), NCI, NIDCR, NIDDK, and NIGMS.
Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages
Reddy et al., Molecular Carcinogenesis. 2026.
https://pubmed.ncbi.nlm.nih.gov/41498201
Macrophages are a type of immune cell that are highly plastic—meaning environmental cues change their phenotype (physical characteristics) and behavior. Cancer cells take advantage of this plasticity to recruit and create tumor-associated macrophages (TAMs) that benefit the tumor microenvironment and promote tumor development. However, the underlying mechanism that cancer cells use to recruit TAMs remains unknown. In this study, researchers used murine and human non-small cell lung cancer cell models to show that integrin αvβ3 expression is needed to drive TAM accumulation. This research highlights a novel mechanism—αvβ3-mediated glutamine secretion—to promote TAM accumulation and begin tumor development. Developing therapies that target this signaling axis could help treat αvβ3-expressing cancers. Supported by ORIP (K01OD030513) and NINDS.
Collagen Pyridinoline Cross-Links Are Absent in Reversible Myocardial Fibrosis
Akam-Baxter, Circulation Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/39717913
Cardiac fibrosis (excessive buildup of collagen around cells in the heart) is a key feature of many heart diseases. Collagen is stabilized by reversible cross-links that mature into degradation-resistant cross-links over time. In this study, researchers used 8- to 10-week-old male mice in a high-fat diet model and a heart attack model of cardiac fibrosis. Results showed that the high-fat diet group had more total collagen in the heart than the control and high-fat diet withdrawal groups. A significantly higher amount of degradation-resistant collagen cross-links were seen in the heart attack group compared with the control and high-fat diet groups. These researchers also found that mature collagen cross-links were absent in regenerating zebrafish hearts. The results from this study support that reversible cardiac fibrosis lacks degradation-resistant cross-links, highlighting a critical component to target when treating heart disease. Supported by ORIP (S10OD032138), NHLBI, and NIDDK.
Concurrent TB and HIV Therapies Control TB Reactivation During Co-Infection but not Chronic Immune Activation
Sharan, Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/41387448
People with HIV (PWH) have a higher rate of morbidity and death caused by tuberculosis (TB). Previous research shows that HIV-driven depletion of CD4+ T cells and chronic immune activation correlates with revival of latent (dormant) TB infection (LTBI) in humans. Using a rhesus macaque model (both sexes used) for LTBI and simian immunodeficiency virus (SIV)—equivalent to HIV but in nonhuman primates—coinfection, researchers studied whether combination antiretroviral therapy (cART) plus weekly isoniazid/rifapentine (3HP) would improve control over bacterial infection and restore the immune system. 3HP plus cART significantly reduced bacterial burden and prevented extrapulmonary dissemination (spread of bacteria to other parts of the body) compared with cART alone. However, this combined treatment failed to fully restore lung CD4+ effector memory T-cell responses or resolve chronic immune activation. Also, immune changes—including type I interferon signature, PD-1 expression, and granulomatous inflammation—persisted. This study highlights a benefit with combination therapy, but immune balance is not fully restored, which is a driver of TB risk in PWH. Supported by ORIP (K01OD031898, U42OD010442, S10OD028732, S10OD030311, and S10OD032443) and NIAID.
Age-Associated Expansion of HIV/SIV Reservoirs in People with HIV and SIV-infected Macaques
Acharya, Aging Cell. 2025.
https://pubmed.ncbi.nlm.nih.gov/41051053
Immune system dysfunction increases with age, and the impact on HIV is not well known. In this retrospective study, researchers used blood samples from young and older people with HIV (PWH) (both sexes used) to quantify intact and total HIV proviral DNA from CD4+ T cells. Results showed that advancing age is associated with expansion and enhanced stability of the replication-competent HIV reservoirs (immune cells infected with HIV but not actively producing new virus particles) in PWH on antiretroviral therapy. Similar findings were seen in male simian immunodeficiency virus (SIV)—equivalent to HIV but in nonhuman primates—infected rhesus macaques. Older PWH had higher levels of intact proviral DNA, reduced reservoir decay, and increased clonal expansion (quick increase in cell number) of infected CD4+ T cells, consistent with age-related immune senescence (immune cells that no longer divide into new cells). The observations in rhesus macaques underscore the critical importance of comparative medicine in parsing mechanisms of HIV viral persistence that cannot be longitudinally or invasively studied in humans. By integrating human and nonhuman primate data, this work strengthens translational insight into how aging impacts HIV cure strategies. Supported by ORIP (R21OD037751), NIDA, and NIMH.
Sucralose Consumption Ablates Cancer Immunotherapy Response Through Microbiome Disruption
Morder, Cancer Discovery. 2025.
https://pubmed.ncbi.nlm.nih.gov/40742298
Sucralose, an artificial sweetener, is common in the Western diet. Sucralose causes changes to the gut microbiome (the collection of different microbes), increases the risk of glucose intolerance, and damages T-cell proliferation (increase in cell numbers). The link among sucralose, the gut microbiome, and cancer immunotherapy outcomes remains unknown. Using cell cultures, 6-week-old female mouse models, and dietary surveys from 157 patients (both sexes used) with advanced cancer, researchers found that sucralose significantly impaired the success of anti-PD-1 immune checkpoint inhibitors against cancer. Sucralose modified the microbiome composition and reduced microbe-accessible arginine (a building block of proteins), which affected the ability of T cells to target and attack cancer cells. These effects are reversible, as arginine supplementation or fecal transfer from treatment-responsive mice restored T cell function and immunotherapy effectiveness in the preclinical cancer model. These findings highlight the role of dietary sucralose in impacting the success of cancer treatments and patient outcomes. Supported by ORIP (S10OD023402, S10OD032141), NCI, NIAID, and NIGMS.
Neonatal Fungi Promote Lifelong Metabolic Health Through Macrophage-Dependent β Cell Development
Hill, Science. 2025.
https://pubmed.ncbi.nlm.nih.gov/40048508
Pancreatic β cells are the only producers of insulin, and diabetes develops when the body does not have adequate levels of insulin. To meet the metabolic demands of a growing infant, the amount of pancreatic β cells rapidly increases. At the same time, the microbiome (the collection of microbes found in the body) expands and is correlated with protecting against childhood diabetes, but the underlying mechanisms by which microbes influence metabolic disease remains poorly known. Using fecal samples from babies (sex not specified) under the age of 1 and newborn mice (sex not specified), the researchers identified a critical window where specific microbes—including Candida dubliniensis—were needed to promote growth of the β cell population. C. dubliniensis promoted macrophage (an immune cell) activity. Destroying the macrophage population prevented the positive effects observed with the β-cell population, highlighting the importance of this immune cell in mediating metabolic health. C. dubliniensis greatly reduced disease severity in 6- to 11-week-old diabetic mouse models (both sexes used). This study emphasizes the importance of microbes in metabolic health and identifies specific windows during growth where pancreatic β-cell development is vital. Supported by ORIP (S10OD026959), NCCIH, NICHD, and NIDDK.
Inducing Ferroptosis to Impede Metastasis by Inhibiting the Calcium Channel TRPC6
Dimitrov et al., Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/41206865
Aggressive cancers such as triple negative breast cancer (TNBC) are able to resist standard chemotherapy and metastasize (spread to other parts of the body) quickly. Previous research shows that the calcium channel TRPC6 helps a subset of cancer cells remain quiescent (a reversable, inactive cell state), which promotes chemotherapy and ferroptosis resistance. Researchers noted that circulating tumor cells isolated from breast cancer patients displayed a higher level of TRPC6 than the primary tumor. Using in vitro (outside of an organism) experiments and 6- and 12-week-old female mice, researchers studied whether the quiescent subset of TNBC cells was sensitive to ferroptosis when targeting TRPC6. Results showed that TRPC6 can cause ferroptosis resistance. The underlying mechanism for ferroptosis resistance was that TRPC6 limits c-Myc to sustain high levels of glutathione. TNBC metastasis was significantly reduced when a TRPC6 inhibitor was used. This study supports a possible opportunity to mitigate TNBC metastasis by targeting TRPC6. Supported by ORIP (K01OD034451) and NCI.