An integrative meningioma surfaceome atlas and a transferable framework for CAR-T target nomination.
- 1Department of Neurosurgery, Stanford University, Stanford, CA, United States.
- 2Geisel School of Medicine, Dartmouth College, Hanover, NH, United States.
- 3Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, United Kingdom.
Abstract
Meningioma is the most common primary intracranial tumor, yet recurrent and high-grade disease has few durable systemic options, and, unlike hematological malignancies, no systematically filtered cell-surface antigen resource exists to guide chimeric antigen receptor (CAR) T development. We address this gap not by nominating a trial-ready target but by building two reusable resources: an integrative meningioma surfaceome atlas and a transferable, gate-based framework that separates transcriptomic discovery from CAR-T target nomination. Analyzing single-cell RNA sequencing from eight meningioma patients (GSE183655; 80,220 quality-controlled cells), patient-aware differential expression followed by a curated surfaceome filter (UniProt plasma-membrane localization; extracellular domain ≥20 aa; exclusion of ribosomal, nuclear, cytoplasmic, and secreted proteins) reduced 83 scored candidates to 13 bona fide plasma-membrane (Tier A) antigens, removing prominent false positives such as the nuclear proteins FOXC1 and MGMT, the cytoplasmic enzyme lactate dehydrogenase A (LDHA), and the secreted protein PTGDS. Because expression ranking establishes discovery but not CAR-T suitability, we then applied explicit nomination gates: a systemic-safety score integrating whole-body GTEx transcriptomics with Human Protein Atlas protein-level evidence; a membrane-topology tractability gate distinguishing antibody-accessible single-pass and GPI-anchored ectodomains from multi-pass transporters and tail-anchored proteins; and a safety × coverage metric. Under stringent thresholds (combined safety ≥0.55, tumor-cell detection fraction ≥50%, safety × coverage ≥0.30), no Tier A antigen qualified. Ubiquitously expressed antigens were correctly demoted, including the tetraspanin CD9 (53.2% tumor-cell coverage but pan-tissue protein expression and high plasma abundance), and the highest-ranked transporter SLC7A2 was demoted by multi-pass topology (largest extracellular loop 38 aa) despite favorable transcriptomic safety. Leukemia inhibitory factor receptor (LIFR), a single-pass type I receptor with a contiguous 789-aa ectodomain, was the only antibody-tractable nominee for experimental follow-up yet remained liability laden (combined safety 0.41; safety × coverage 0.135) and is not a validated target. Cross-dataset expression overlap (93.3%) reflected mRNA reproducibility, not CAR-T validity or clinical validation, and generic-antibody docking was exploratory only. All findings are transcriptomic and require surface-level confirmation. This work contributes a reproducible meningioma surfaceome atlas and a transferable nomination framework and shows that rigorous gating leaves no single antigen with a favorable safety × coverage × tractability profile, motivating bispecific and logic-gated CAR-T strategies.
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BibTeX
@article{sanker2026integrative,
title = {{An integrative meningioma surfaceome atlas and a transferable framework for CAR-T target nomination.}},
author = {Vivek Sanker and Dhanya Mahesh and Linda Liverani and Matthew Alexander Abikenari and Zhikai Li and Yi Zhang and Debebe Theodros and Ravi Medikonda and Maria Jose Cavagnaro and Matei Alexandru Banu and Atman Desai and Michael Lim},
journal = {Frontiers in bioinformatics},
year = {2026},
month = oct,
doi = {10.3389/fbinf.2026.1919802},
url = {https://europepmc.org/article/MED/42898508},
note = {CC BY},
}
RIS
TY - JOUR
TI - An integrative meningioma surfaceome atlas and a transferable framework for CAR-T target nomination.
AU - Vivek Sanker
AU - Dhanya Mahesh
AU - Linda Liverani
AU - Matthew Alexander Abikenari
AU - Zhikai Li
AU - Yi Zhang
AU - Debebe Theodros
AU - Ravi Medikonda
AU - Maria Jose Cavagnaro
AU - Matei Alexandru Banu
AU - Atman Desai
AU - Michael Lim
PY - 2026
DA - 2026/10/05
JO - Frontiers in bioinformatics
DO - 10.3389/fbinf.2026.1919802
UR - https://europepmc.org/article/MED/42898508
AB - Meningioma is the most common primary intracranial tumor, yet recurrent and high-grade disease has few durable systemic options, and, unlike hematological malignancies, no systematically filtered cell-surface antigen resource exists to guide chimeric antigen receptor (CAR) T development. We address this gap not by nominating a trial-ready target but by building two reusable resources: an integrative meningioma surfaceome atlas and a transferable, gate-based framework that separates transcriptomic discovery from CAR-T target nomination. Analyzing single-cell RNA sequencing from eight meningioma patients (GSE183655; 80,220 quality-controlled cells), patient-aware differential expression followed by a curated surfaceome filter (UniProt plasma-membrane localization; extracellular domain ≥20 aa; exclusion of ribosomal, nuclear, cytoplasmic, and secreted proteins) reduced 83 scored candidates to 13 bona fide plasma-membrane (Tier A) antigens, removing prominent false positives such as the nuclear proteins FOXC1 and MGMT, the cytoplasmic enzyme lactate dehydrogenase A (LDHA), and the secreted protein PTGDS. Because expression ranking establishes discovery but not CAR-T suitability, we then applied explicit nomination gates: a systemic-safety score integrating whole-body GTEx transcriptomics with Human Protein Atlas protein-level evidence; a membrane-topology tractability gate distinguishing antibody-accessible single-pass and GPI-anchored ectodomains from multi-pass transporters and tail-anchored proteins; and a safety × coverage metric. Under stringent thresholds (combined safety ≥0.55, tumor-cell detection fraction ≥50%, safety × coverage ≥0.30), no Tier A antigen qualified. Ubiquitously expressed antigens were correctly demoted, including the tetraspanin CD9 (53.2% tumor-cell coverage but pan-tissue protein expression and high plasma abundance), and the highest-ranked transporter SLC7A2 was demoted by multi-pass topology (largest extracellular loop 38 aa) despite favorable transcriptomic safety. Leukemia inhibitory factor receptor (LIFR), a single-pass type I receptor with a contiguous 789-aa ectodomain, was the only antibody-tractable nominee for experimental follow-up yet remained liability laden (combined safety 0.41; safety × coverage 0.135) and is not a validated target. Cross-dataset expression overlap (93.3%) reflected mRNA reproducibility, not CAR-T validity or clinical validation, and generic-antibody docking was exploratory only. All findings are transcriptomic and require surface-level confirmation. This work contributes a reproducible meningioma surfaceome atlas and a transferable nomination framework and shows that rigorous gating leaves no single antigen with a favorable safety × coverage × tractability profile, motivating bispecific and logic-gated CAR-T strategies.
SN - 2673-7647
ER -