Omics · study · 2026
IFNγ-induced antigen loss in chimeric antigen receptor (CAR)-T cell therapy
Listed in NCBI GEO
FDA-approved chimeric antigen receptor (CAR)-expressing T cell therapies (CARTs) have revolutionized the treatment of blood cancers.
Description
Yet none have been successful for “solid” tumors, such as colorectal cancer (CRC), the 2nd leading cause of cancer deaths. Guanylyl cyclase C (GUCY2C) has emerged as a clinical-stage target for CART and bispecific T-cell engager (BiTE) therapies in CRC.
Here, we identified a novel antigen loss mechanism that limits the efficacy of CART in CRC, in which IFNγ secreted by activated CART cells causes bystander cancer cells to lose GUCY2C. Moreover, this previously unexplored antigen loss mechanism is mediated through IFNγR (receptor)/JAK and cellular stress signaling pathways. This newly discovered mechanism of antigen loss can be rescued with anti-IFNγ neutralizing antibody, the JAK inhibitor ruxolitinib, or 4-phenylbutyrate (an ER stress reliever).
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IFNγ has been canonically recognized as beneficial for the effector functions of T cells by enhancing antigen processing and HLA presentation and is essential for CART targeting of solid malignancies by inducing adhesion molecule expression for synapse stabilization. Here, we revealed a negative effect of IFNγ that uniquely interferes with immunotherapies targeting native surface antigens, such as CART and BiTE therapies, which may be reversed by disrupting stress signaling pathways to enhance solid tumor CART and BiTE immunotherapies.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE322nnn/GSE322823 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE322823 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1431917 ncbi.nlm.nih.gov/bioproject/PRJNA1431917 ↗
project · from NCBI GEO
- PubMed 41924255 pubmed.ncbi.nlm.nih.gov/41924255 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75%
Provenance · 1 source records, 8 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE322823 | 11 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |