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8 Publications visible to you, out of a total of 8
Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies.

Abstract (Expand)

Tyrosine kinases (TKs) are frequently mutated or overexpressed in cancer, and TK inhibitors (TKIs) are an important therapeutic modality against TK-driven cancers, but many patients show an underwhelming … response to TKIs prescribed on the basis of tumor genotype. To find cell-intrinsic TK signaling patterns which might be predictive of poor response to TKI therapies, we used high-sensitivity multiplexed mass spectrometry to quantify endogenous levels of 1,222 phosphotyrosine (pY) sites across the proteomes of TK-driven human cancer cell lines with variable response to genotype-matched TKIs. In direct comparisons between TKI-tolerant and TKI-sensitive lines with a common driver TK, we found that TKI treatment was equally effective at blocking driver TK signaling, and higher basal activity of the driver TK did not always predict higher sensitivity to TKI. All tolerant lines showed a dampened proteome-wide pY response to TKI exposure compared to sensitive lines, suggesting that tumor cells with more robust TK signaling are less vulnerable to driver TK blockade. We found that each tolerant line depends on a unique set of compensatory TKs and signaling axes but are unified by hyperactivity of at least one of the SRC family kinases (SFKs) or the related ABL1/2 kinases, both at rest and under TKI treatment, despite the absence of SFK or ABL genetic mutations. In time- and dose-resolved drug combination experiments, SFK/ABL inhibitors were potently synergistic with all TKIs tested, demonstrating that elevated SFK/ABL signaling is a conserved bottleneck for maximal TKI efficacy which could be exploited therapeutically.

Authors: C. T. Flower, F. M. White

Date Published: 31st Mar 2026

Publication Type: Journal

Quantitative Cell Type-Specific Immunopeptidome Analysis of Macrophage and Tumor Coevolution Reveals Therapeutic MHC-I Peptides in Glioblastoma.

Abstract (Expand)

Immune checkpoint inhibitors have shown impressive performance in treating several types of solid tumors. However, they have been ineffective in glioblastoma (GBM), in part due to the immunosuppressive … tumor microenvironment created by GBM-associated macrophages (GAM). To uncover MHC-I peptide antigens for targeted immunotherapy, we performed cell type-specific immunopeptidome analysis on primary macrophages and GBM tumor cells in a coculture system to profile MHC-I-associated antigen presentation at the tumor-macrophage interface. Coculturing tumor cells and macrophages induced increased presentation of peptides derived from proteins associated with cytokine signaling pathways on macrophages and from proteins associated with the Rho GTPase pathway on GBM tumor cells. In vivo expression was validated for a cohort of coculture-induced GAMs or GBM-associated peptides selected as potential immunotherapy targets, and an mRNA vaccine was developed encoding six peptides from GAMs and GBM tumor cells. Two doses of vaccination generated an antigen-specific immune response, significantly delayed GBM tumor growth, and in some cases eradicated tumors. These results demonstrate the translational potential of coculture-induced MHC peptide antigens as therapeutic targets for GBM/GAM-targeting vaccines. SIGNIFICANCE: Immunopeptidomic analysis identified altered expression of antigens during macrophage-tumor coevolution that could be targeted with an mRNA vaccine to significantly inhibit glioblastoma growth, revealing potential immunotherapeutic strategies for treating tumors.

Authors: Y. Cui, K. Phuong, N. S. Abdelfattah, H. M. Temple, L. Maiorino, B. J. Kim, J. Dye, K. K. H. Yu, S. Spranger, D. J. Irvine, F. M. White

Date Published: 15th Dec 2025

Publication Type: Journal

Immunopeptidomics can inform the design of mRNA vaccines for the delivery of Mycobacterium tuberculosis MHC class II antigens.

Abstract (Expand)

No currently licensed vaccine reliably prevents pulmonary tuberculosis (TB), a leading cause of infectious disease mortality. Developing effective new vaccines requires identifying which Mycobacterium … tuberculosis (Mtb) proteins are presented on major histocompatibility complex class II (MHC-II) by infected human phagocytes (target cells) and defining their capacity for recognition by CD4(+) T cells. Vaccine designs must elicit T cell responses recognizing the same peptide-MHC complexes presented by infected cells. Although many human CD4(+) T cell Mtb epitopes have been described, presentation on MHC-II by infected cells in most cases has not been directly evaluated. Using mass spectrometry (MS), we demonstrated that Mtb type VII secretion system (T7SS) substrates are enriched in the MHC-II repertoire of Mtb-infected human monocyte-derived phagocytes and that many of these antigens are immunogenic in people with prior evidence of Mtb infection. We next used MS to guide TB messenger RNA (mRNA) vaccine design, increasing the presentation of target MHC-II epitopes by orders of magnitude by incorporating design features that mirror aspects of antigen presentation dynamics in infected phagocytes. Our results provide a strategy for TB vaccine design that is guided by bottom-up unbiased discovery. Our approach combines targeted evaluation of antigen presentation in human cells paired with rapid iterative testing of mRNA vaccine designs to optimize antigen presentation before animal studies or human clinical trials.

Authors: O. Leddy, P. Ogongo, J. Huffaker, M. Gan, R. Milligan, S. Mahmud, H. M. Ni, Y. Yuki, K. Bobosha, L. Wassie, M. Carrington, Q. Liu, J. D. Ernst, F. M. White, B. D. Bryson

Date Published: 5th Nov 2025

Publication Type: Journal

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

Abstract (Expand)

The brain avidly consumes glucose to fuel neurophysiology(1). Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy … tissue(2). How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused (13)C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Authors: A. J. Scott, A. Mittal, B. Meghdadi, A. O'Brien, J. Bailleul, P. Sravya, A. Achreja, W. Zhou, J. Xu, A. Lin, K. Wilder-Romans, N. Liang, A. U. Kothari, N. Korimerla, D. M. Edwards, Z. Wu, J. Feng, S. Su, L. Zhang, P. Sajjakulnukit, A. C. Andren, J. O. Park, J. Ten Hoeve, V. Tarnal, K. A. Redic, N. R. Qi, J. L. Fischer, E. Yang, M. S. Regan, S. A. Stopka, G. Baquer, K. Suresh, J. N. Sarkaria, T. S. Lawrence, S. Venneti, N. Y. R. Agar, E. Vlashi, C. A. Lyssiotis, W. N. Al-Holou, D. Nagrath, D. R. Wahl

Date Published: 9th Oct 2025

Publication Type: Journal

Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery.

Abstract (Expand)

Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobial-resistant (AMR) microbial pathogens and viruses with pandemic … potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on MHCs can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self-peptides in the MHC repertoire and may be missed in untargeted MS analyses. Here, we present a novel approach, termed PathMHC, that uses computational analysis of untargeted MS data followed by targeted MS to discover novel pathogen-derived MHC peptides more efficiently than untargeted methods alone. We applied this workflow to identify MHC peptides derived from multiple microbes, including potential vaccine targets presented on MHC-I by human dendritic cells infected with Mycobacterium tuberculosis (Mtb), finding that all Mtb peptides detected in the MHC-I repertoire derived from proteins exported by type VII secretion systems. PathMHC will facilitate antigen discovery campaigns for vaccine development.

Authors: O. Leddy, Y. Yuki, M. Carrington, B. D. Bryson, F. M. White

Date Published: 6th Oct 2025

Publication Type: Journal

Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.

Abstract (Expand)

Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic … mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.

Authors: T. Y. Tamir, S. Chaudhary, A. X. Li, S. E. Trojan, C. T. Flower, P. Vo, Y. Cui, J. C. Davis, R. Mukkamala, F. N. Venditti, A. L. Hillis, A. Toker, M. G. Vander Heiden, J. B. Spinelli, N. J. Kennedy, R. J. Davis, F. M. White

Date Published: 5th Jun 2025

Publication Type: Journal

Validation and quantification of peptide antigens presented on MHCs using SureQuant.

Abstract (Expand)

Vaccines and immunotherapies that target peptide-major histocompatibility complexes (peptide-MHCs) have the potential to address multiple unmet medical needs in cancer and infectious disease. Designing … vaccines and immunotherapies to target peptide-MHCs requires accurate identification of target peptides in infected or cancerous cells or tissue, and may require absolute or relative quantification to identify abundant targets and measure changes in presentation under different treatment conditions. Internal standard parallel reaction monitoring (also known as 'SureQuant') can be used to validate and/or quantify MHC peptides previously identified by using untargeted methods such as data-dependent acquisition. SureQuant MHC has three main use cases: (i) conclusive confirmation of the identities of putative MHC peptides via comparison with an internal synthetic stable isotope labeled (SIL) peptide standard; (ii) accurate relative quantification by using pre-formed heavy isotope-labeled peptide-MHC complexes (hipMHCs) containing SIL peptides as internal controls for technical variation; and (iii) absolute quantification of each target peptide by using different amounts of hipMHCs loaded with synthetic peptides containing one, two or three SIL amino acids to provide an internal standard curve. Absolute quantification can help determine whether the abundance of a peptide-MHC is sufficient for certain therapeutic modalities. SureQuant MHC therefore provides unique advantages for immunologists seeking to confidently validate antigenic targets and understand the dynamics of the MHC repertoire. After synthetic standards are ordered (3-4 weeks), this protocol can be carried out in 3-4 days and is suitable for individuals with mass spectrometry experience who are comfortable with customizing instrument methods.

Authors: O. Leddy, Y. Cui, R. Ahn, L. Stopfer, E. Choe, D. H. Kim, M. Roerden, S. Spranger, B. D. Bryson, F. M. White

Date Published: 13th May 2025

Publication Type: Journal

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