In Vivo Target Identification and Machine Learning Validation of Autoimmune T Cell Tissue Residence

Identifying GSPT1 as an essential, targetable vulnerability of skin-resident memory T cells to enable durable remission in chronic inflammatory skin diseases without systemic immunosuppression.
Completed Allergic & Atopic Diseases Dermatologic Diseases Psoriasis Vitiligo Adaptive Immunity Biological & Mechanistic Data-Driven & Quantitative Drug Repurposing Experimental Platforms & Models Functional Genomics & CRISPR In Vitro Models Machine Learning & AI T Cell Biology Therapeutic Development Translational & Clinical

Funding Year: 2022

Project Overview

Chronic inflammatory skin diseases like psoriasis, vitiligo, and eczema relapse because tissue-resident memory T cells (TRM) persist in the skin between flares, ready to reignite inflammation. Current therapies broadly suppress the immune system without eliminating these cells. Through a first-ever genome-wide CRISPR screen in human T cells differentiating in human skin, this project identified GSPT1 — a translation termination factor — as essential for TRM survival but dispensable for circulating T cells. Treatment with the clinical-stage GSPT1 degrader CC90009 reduced TRM viability by over 80% at doses that spared circulating T cells. Additional innovations include a human xenograft model with single-cell multiome sequencing, spatial transcriptomics, and intravital imaging, as well as targeted lipid nanoparticles conjugated with anti-CD5 antibodies for tissue-specific TRM delivery.

Impact & Innovation

A targetable metabolic vulnerability hiding in the skin

 

GSPT1-mediated translation efficiency is essential for TRM survival but dispensable for circulating T cells — making it a clinically actionable target that could eliminate the hidden drivers of disease recurrence without compromising systemic immunity.

  • Identifies GSPT1 as the first clinically actionable, TRM-specific therapeutic target, with CC90009 already in human trials and demonstrating selective TRM depletion at a viable therapeutic window
  • Generates IP through a patent application for methods affecting tissue-resident T cells filed April 2025, with grants pending to advance toward clinical translation
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a novel tissue-specific metabolic dependency from CRISPR discovery through nanoparticle delivery development toward clinical trials in psoriasis, vitiligo, and eczema
Research Approach

A framework designed for discovery

This project combines genome-wide CRISPR screening in human skin, advanced xenograft modeling, and targeted nanoparticle delivery development to identify and validate GSPT1 as a TRM-specific therapeutic target in chronic inflammatory skin diseases. The work moves from in vivo target discovery through mechanistic characterization and translational delivery system development.

First-ever genome-wide in vivo CRISPR screen in human T cells differentiating within human skin xenografts; single-cell multiome sequencing (>240,000 cells profiled); spatial transcriptomics and intravital imaging to track T cell decisions in native tissue architecture; GSPT1 degrader (CC90009) treatment studies measuring differential TRM vs. circulating T cell viability; and development and validation of lipid nanoparticles conjugated with anti-CD5 antibodies for tissue-specific TRM-targeted genetic cargo delivery.

Human skin xenograft models with genome-wide CRISPR screening datasets; single-cell multiome and spatial transcriptomic datasets from >240,000 profiled T cells; GSPT1 inhibition datasets measuring polysome:monosome ratios and translation efficiency in TRM vs. circulating T cells; and in vivo LNP delivery validation datasets confirming >90% delivery efficiency to skin-resident T cells.

Validation of GSPT1 as a clinically actionable, TRM-specific vulnerability enabling selective elimination of disease-causing resident T cells without systemic immunosuppression, with translation accelerated by CC90009’s existing clinical-stage status. A patent application was filed April 2025, grants are pending, and the work is positioned to advance rapidly toward clinical trials in psoriasis, vitiligo, and eczema.

Investigators & Institutions

Powering the science

Principal Investigator

Christoph Ellebrecht, MD, Colton Consortium Member

Assistant Professor, Department of Dermatology, Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Publications

Divergent ontogeny of tissue resident memory and tissue resident exhausted CD8+ T cells underlies distinct functional potential

bioRxiv [Preprint]
Park, SL; Painter, MM; Manne, S; Alcalde, V; McLaughlin, M; Sullivan, MA; Mathew, D; Torres, L; Huang, YJ; Reeg, DB; Douek, NR; Campos, T; Klapholz, M; Cardenas, MA; Fang, V; Ngiow, SF; Kc, W; Goel, RR; Baxter, AE; Wu, JE; Tan, M; Berry, CT; Ellebrecht, CT; Huang, AC; Papazian, E; Liu, Y; Rajasekaran, K; Brody, RM; Thaler, ER; Basu, D; Diab, A; Giles, JR; Wherry, EJ August 2025
Adaptive ImmunityAnimal ModelsBiological & MechanisticExperimental Platforms & ModelsImmune DevelopmentImmune ProfilingSingle Cell TechnologiesT Cell BiologyOtherUniversity of Pennsylvania

Fate induction in CD8 CAR T cells through asymmetric cell division

Nature
Lee, CS; Chen, S; Berry, CT; Kelly, AR; Herman, PJ; Oh, S; O'Connor, RS; Payne, AS; Ellebrecht, CT August 2024
Adaptive ImmunityAnimal ModelsBiological & MechanisticExperimental Platforms & ModelsIn Vitro ModelsSingle Cell TechnologiesT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalOtherUniversity of Pennsylvania

Additional Outputs

Genome-wide in vivo CRISPR screen reveals GSPT1 as an essential regulator of human T cell tissue residency. 

Patent application filed 4/28/2025: Methods for affecting tissue-resident T cells.