Evidence map›Paper›PMID 41040261›Full record

ArticlebioRxiv : the preprint server for biology2025

In vivo genome-wide CRISPR screens in human T cells to enhance T cell therapy for solid tumors.

Qi Liu, Peixin Amy Chen, Esha Urs, Shimin Zhang, Maya M Arce, Charlotte H Wang, Zhongmei Li, Jin Seo, Nupura Kale, Taylor N LaFlam and 9 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Qi LiuDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Peixin Amy ChenDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Esha UrsDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Shimin ZhangDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Maya M ArceDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Charlotte H WangDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Zhongmei LiDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Jin SeoDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Nupura KaleDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Taylor N LaFlamDivision of Pediatric Rheumatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
Fanglue PengDepartment of Microbiology and Immunology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
Eric ShifrutGray Faculty of Medical and Health Sciences, Tel Aviv University, Israel.
Greg M AllenDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Justin EyquemDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Katherine FuhDepartment of OB/Gyn and Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
Stacie E DodgsonGladstone Institutes, San Francisco, CA, USA.
Jason G CysterDepartment of OB/Gyn and Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
Alexander MarsonDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Julia CarnevaleDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0001-9410-7148

Funding

UCSF Nutrition Obesity Research CenterP30DK098722 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Allison W Xu · 2015 to 2026
$14.6M
Restorative practice in repairing harm and promoting safe and inclusive practices in the laboratory.T32GM136547 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Adrian Erlebacher, Anita Sil · 2020 to 2026
$4.5M
Developing novel CAR T cell designs using combinatorial antigen detectionK08CA259610 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ALLEN, GREG MANESS · 2021 to 2025
$1.4M
NCI NIH HHS K08 CA259610NIDDK NIH HHS P30 DK098722NIGMS NIH HHS T32 GM136547
6 · The paper itself

Abstract

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that can enhance cellular immunotherapy. However, many genetic regulators of T cell performance in solid tumors may not be readily revealed in vitro. In vivo screening in tumor-bearing mice offers greater physiological relevance, but has historically been limited by low intratumoral T cell recovery. Here, we developed a new model system that achieves significantly higher human T cell recovery from tumors, enabling genome-wide in vivo screens with small numbers of mice. Tumor-infiltrating T cells in this model exhibit hallmarks of dysfunction compared to matched splenic T cells, creating an ideal context for screening for genetic modifiers of T cell activity in the tumor microenvironment. Using this platform, we performed two genome-wide CRISPR knockout screens to identify genes regulating T cell intratumoral abundance and effector function (e.g., IFN-γ production). The intratumoral abundance screen uncovered the P2RY8-Gα13 GPCR signaling pathway as a negative regulator of human T cell infiltration into tumors. The effector function screen identified GNAS (Gαs), a central signaling mediator downstream of multiple GPCRs that sense different suppressive ligands, as a key regulator of T cell dysfunction in tumors. Targeted GNAS knockout rendered T cells resistant to multiple suppressive cues and significantly improved therapeutic performance across diverse solid tumor models. Moreover, combinatorial knockout of P2RY8 (trafficking) and GNAS (effector function) further enhanced overall tumor control, demonstrating that genetic modifications targeting distinct T cell phenotypes can be combined to improve therapeutic potency. This flexible and scalable in vivo screening platform can be adapted to diverse tumor models and pooled CRISPR libraries, enabling future discovery of genetic strategies that equip T cell therapies to overcome barriers imposed by solid tumors.

Identifiers

PMID41040261
PMCPMC12485727

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.