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SEEK ID: https://nextseek-dev.mit.edu/investigations/1

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Created: 21st Jan 2026 at 15:07

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Institutions: BMC-BioMicro Center (MIT)

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

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*Tigist Y Tamir 1,2,3,6, Shreya Chaudhary 1,6, Annie X Li 1,6, Sonia E Trojan 1,4,6 3 , Cameron T Flower 1,2,5,6, Paula Vo 7 , Yufei Cui 1,3,6, Jeffrey C Davis1,4,6, Rachit S Mukkamala 1,3,6 4 , Francesca N Venditti 1,6, Alissandra L Hillis 8 , Alex Toker 8 , Matthew G Vander Heiden 1,2,4,6,7 5 , Jessica B Spinelli 9 , Norman J Kennedy 9 , Roger J Davis 9 , and *Forest M White 1,2,3,5,6

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DOI: https://www.biorxiv.org/content/10.1101/2024.08.28.609894v1.full

Abstract: Coordination of adaptive ...

Submitter: Demo Demo

Investigation: CSBC

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Created: 22nd Jan 2026 at 20:17

Validation and quantification of peptide antigens presented on MHCs using SureQuant

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Owen Leddy, Yufei Cui, Ryuhjin Ahn, Lauren Stopfer, Elizabeth Choe, Do Hun Kim, Malte Roerden, Stefani Spranger, Bryan D. Bryson & Forest M. White

DOI: https://www.nature.com/articles/s41596-024-01076-x#Sec43

Abstract: 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 ...

Submitter: Demo Demo

Investigation: CSBC

Assays: ImmunoPeptideomics - Data Linked, Sample Processing - Metadata, SureQuant Analysis - Data Linked

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Created: 21st Jan 2026 at 15:07

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Sample Processing - Metadata

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Investigation: CSBC

Study: Validation and quantification of peptide antige...

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SOPs: P.WHI-250319-V1_SureQuant_SampleProcessing.docx

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Created: 21st Jan 2026 at 15:08, Last updated: 22nd Jan 2026 at 20:31

ImmunoPeptideomics - Data Linked

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Study: Validation and quantification of peptide antige...

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SOPs: P.WHI-250319-V1_SureQuant_Protocol.pdf

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Created: 21st Jan 2026 at 15:08, Last updated: 22nd Jan 2026 at 16:26

SureQuant Analysis - Data Linked

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Study: Validation and quantification of peptide antige...

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SOPs: P.WHI-250319-V1_SureQuant_Protocol.pdf

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Created: 21st Jan 2026 at 15:08, Last updated: 22nd Jan 2026 at 16:26

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P.WHI-250319-V1_SureQuant_SampleProcessing.docx

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Studies: Validation and quantification of peptide antige...

Assays: Sample Processing - Metadata

Created: 22nd Jan 2026 at 20:31, Last updated: 22nd Jan 2026 at 20:31

P.WHI-250319-V1_SureQuant_Protocol.pdf

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Studies: Validation and quantification of peptide antige...

Assays: ImmunoPeptideomics - Data Linked, SureQuant Analysis - Data Linked

Created: 22nd Jan 2026 at 16:26, Last updated: 22nd Jan 2026 at 16:26

Showing 5 out of a possible 8 Publications Advanced Publications list for this Investigation with search and filtering

Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies.

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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

PubMed ID: 41880579

DOI: 10.1073/pnas.2522090123

Citation: Proc Natl Acad Sci U S A. 2026 Mar 31;123(13):e2522090123. doi: 10.1073/pnas.2522090123. Epub 2026 Mar 25.

Created: 25th Aug 2026 at 19:19

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

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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

PubMed ID: 40966317

DOI: 10.1158/0008-5472.can-24-4674

Citation: Cancer Res. 2025 Dec 15;85(24):4958-4976. doi: 10.1158/0008-5472.CAN-24-4674.

Created: 25th Aug 2026 at 19:22

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

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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

PubMed ID: 41191777

DOI: 10.1126/scitranslmed.adw9184

Citation: Sci Transl Med. 2025 Nov 5;17(823):eadw9184. doi: 10.1126/scitranslmed.adw9184. Epub 2025 Nov 5.

Created: 25th Aug 2026 at 19:22

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

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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

PubMed ID: 40903569

DOI: 10.1038/s41586-025-09460-7

Citation: Nature. 2025 Oct;646(8084):413-422. doi: 10.1038/s41586-025-09460-7. Epub 2025 Sep 3.

Created: 25th Aug 2026 at 19:21

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

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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

PubMed ID: 40689854

DOI: 10.1084/jem.20250444

Citation: J Exp Med. 2025 Oct 6;222(10):e20250444. doi: 10.1084/jem.20250444. Epub 2025 Jul 21.

Created: 25th Aug 2026 at 19:23

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