Biology subjects

O'Hara, J.

Publications and source records attributed to O'Hara, J..

3 recordsLinked to original sources

bioRxiv2026

PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis

Metastasis remains the leading cause of cancer mortality, yet effective therapies are limited. While therapeutic responses are influenced by organ-specific immune microenvironments, strategies to pharmacologically modulate these niches remain poorly defined. Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrate that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state. Integrated single-cell/spatial transcriptomics and functional assays reveal that AC484 promotes AM accumulation within metastatic lesions, elevates their IFN{gamma} production and responsiveness, and enhances their tumor-killing activity. Depletion of AMs diminishes the anti-metastatic efficacy of AC484. Mechanistically, inhibiting PTPN1/2 by AC484 amplifies IFN{gamma}-STAT1 signaling in AMs, while disrupting this pathway impairs their tumor control capability. These findings delineate a distinct innate immune axis where PTPN1/2 acts as a molecular "brake" on AM activation, suggesting that pharmacologically unleashing tissue-resident macrophages offers a therapeutic strategy to overcome metastatic progression, particularly in microenvironments where adaptive immunity is insufficient. SignificanceAMs are potent anti-metastatic immune effectors functionally constrained by PTPN1/2. Pharmacologically inhibiting PTPN1/2 amplifies their IFN{gamma}-STAT1 signaling and tumoricidal activity, establishing a strategy to reactivate tissue-resident immunity against metastasis.

immunology↗

bioRxiv2025

SATB1 maintains naive-like identity in antiviral CD8⁺ T cells by limiting chromatin remodelling at effector gene loci.

Optimal CD8+ T cell differentiation requires the engagement of transcriptional programs that drive effector phenotypes and function, whilst also shutting down transcriptional programs that maintain the naive state. While the distinct factors that underpin each state are well studied, the molecular mechanisms that control the switch from the naive to effector state are not fully understood. Utilising integrated analysis of single-cell genomic data, we identified CD8+ T cell effector transcriptional networks that are restrained in the naive state by the chromatin binding protein Special AT-rich sequence binding protein-1 (SATB1). Utilising a SATB1-Tg model, whereby activated CD8+ T cells are unable to down regulate SATB1 upon activation, we observed limited effector differentiation and an inability to engage effector programs in response to both primary and secondary influenza A virus infection. Mechanistically, SATB1 limited chromatin remodelling at key gene loci required for the full engagement of the CD8+ T cell effector program. Hence, SATB1 is a master gatekeeper that maintains the naive T cell state and whose downregulation is necessary to allow transition from a naive to effector state upon T cell activation. SATB1 modulation may provide new strategies for improving CD8+ T cell longevity and self-renewal capacity in different immunotherapeutic treatments.

immunology↗

bioRxiv2021

A thermodynamic model for interpreting tryptophan excitation-energy-dependent fluorescence spectra provides insight into protein conformational sampling and stability

It is now over thirty years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. Whilst there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the protein REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides to multi-tryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibody in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating bimolecular simulation with experimental data to yield novel insights.

biophysics↗