Biology subjects

O'Sullivan, T. E.

Publications and source records attributed to O'Sullivan, T. E..

5 recordsLinked to original sources

bioRxiv2026

Restoration of deficient IL-15 signaling enhances innate lymphoid cell immunity in brain metastasis

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s), collectively known as group 1 innate lymphoid cells (ILCs), are critical mediators of anti-tumor immunity, yet their role in brain metastasis remains poorly defined. Using single-cell RNA sequencing and functional depletion models, we show that group 1 ILCs fail to provide adequate tumor control in breast cancer brain metastasis (BCBM). In contrast to the liver, where diverse, functionally competent group 1 ILC populations facilitate excellent metastatic control, group 1 ILCs in BCBM show limited diversity and profound tissue-specific dysfunction such that their depletion had no effect on tumor burden despite modest parenchymal infiltration. We attribute this group 1 ILC dysfunction to severely restricted IL-15 availability, with IL-15R protein detected at 500-fold lower concentration in the brain than in the liver. Local IL-15 complex administration restored group 1 ILC accumulation, cytotoxicity, and tissue residency, significantly reducing brain metastatic burden independent of T cells. Intracranial delivery of IL-15-secreting induced pluripotent stem-cell-derived (iPSC)-NK cells, already in clinical testing for non-small cell lung cancer, significantly reduced tumor burden. Collectively, these findings reveal how tissue-specific differences in cytokine availability shape group 1 ILC population diversity and disease response, establishing localized IL-15 signaling as a compelling strategy to unlock innate immunity against intracranial malignancies.

immunology↗

bioRxiv2026

The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.

Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.

immunology↗

bioRxiv2026

The Histone Methyltransferase KMT2D promotes Natural Killer cell effector molecule release

Natural Killer (NK) cells eliminate virally infected and cancerous cells by secreting cytotoxic granules and pro-inflammatory cytokines. However, the epigenetic mechanisms that coordinate these processes in human NK cells remain poorly understood. We identified two NK deficiency (NKD) patients with mutations in the histone methyltransferase KMT2D that demonstrated impaired cytotoxicity and degranulation. CRISPR-mediated KMT2D deletion or introduction of a patient-specific mutation in healthy human NK cells was sufficient to inhibit effector functions. NK cell-specific KMT2D deletion in mice resulted in defective NK cell degranulation and IFN-{gamma} production, increasing mortality following MCMV infection. KMT2D loss reduced H3K4me1 deposition, associated with decreased levels of RAB3D. RAB3D-deficient human NK cells reduced the release of GZMB and IFN-{gamma}, without impacting intracellular levels. Thus, KMT2D acts as a conserved epigenetic regulator of mature NK cell functions, promoting rapid effector molecule release.

immunology↗

bioRxiv2022

Sex differences in NK cells mediated by the X-linked epigenetic regulator UTX

Viral infection outcomes are sex-biased, with males generally more susceptible than females. Paradoxically, the numbers of anti-viral natural killer (NK) cells are increased in males compared to females. Using samples from mice and humans, we demonstrate that while numbers of male NK cells are increased compared to females, they display impaired production of the anti-viral cytokine IFN-{gamma}. These sex differences were not due solely to divergent levels of gonadal hormones, since these differences persisted in gonadectomized mice. Instead, these differences can be attributed to lower male expression of X-linked Kdm6a (UTX), an epigenetic regulator which escapes X inactivation in female NK cells. NK cell-specific UTX deletion in females phenocopied multiple features of male NK cells, which include increased numbers and reduced IFN-{gamma} production. Integrative ATAC-seq and RNA-seq analysis revealed a critical role for UTX in the regulation of chromatin accessibility and gene expression at loci important in NK cell homeostasis and effector function. Consequently, NK cell-intrinsic UTX levels are critical for optimal anti-viral immunity, since mice with NK cell-intrinsic UTX deficiency show increased lethality to mouse cytomegalovirus (MCMV) challenge. Taken together, these data implicate UTX as a critical molecular determinant of NK cell sex differences and suggest enhancing UTX function as a new strategy to boost endogenous NK cell anti-viral responses.

immunology↗

bioRxiv2020

NK cells promote cancer immunoediting through tumor-intrinsic loss of interferon-stimulated gene expression

Natural killer (NK) cells are innate lymphocytes that constantly patrol host tissues against transformed cells in a process known as cancer immunosurveillance. Previous evidence in mice has demonstrated that NK cell-derived IFN-{gamma} can promote immunoevasion by sculpting the immunogenicity of developing tumors in a process known as cancer immunoediting. This process involves the elimination of highly immunogenic "unedited" tumor cells followed by the eventual escape of less immunogenic "edited" tumor cell variants that are able to escape recognition or elimination by the immune system. Here, we show that NK cell-edited fibrosarcomas decrease the expression of 17 conserved IFN-{gamma}-inducible genes compared to unedited tumor cells. High expression of 3 of these identified genes (Psmb8, Trim21, Parp12) in human tumor samples correlates with enhanced survival in breast cancer, melanoma, and sarcoma patients. While NK cell-edited fibrosarcomas displayed resistance to IFN-{gamma} growth suppression in vitro, functional knockouts of individual interferon stimulated genes (ISGs) were not required for outgrowth of unedited tumor cell lines in vitro and in vivo compared to complete loss of IFN signaling. Furthermore, knockout of IFN-{gamma}-intrinsic signaling via deletion of Ifngr in edited B16 F10 and E0771 LMB metastatic cancer cell lines did not impact host survival following lung metastasis. Together, these results suggest that unedited tumors can be selected for decreased IFN-{gamma} signaling to evade immune responses in vivo, and as a consequence, tumor-extrinsic IFN signaling may be more important for potentiating durable anti-tumor responses to advanced solid tumors.

immunology↗