Excel · study · 2026
CD73 inhibition overcomes adaptive immune resistance to PARP inhibition in models of prostate cancer
Listed in NCBI GEO
Metastatic castration-resistant prostate cancer (mCRPC) remains a major cause of cancer-related mortality in the male population.
Description
While poly(ADP-ribose) polymeraseinhibitors (PARPi) are approved for selected mCRPC patients with homologous recombination repair (HRR) deficiencies, combinations with PD-1/PD-L1 inhibitors immunotherapy have demonstrated limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARPi in an unbiased manner, we performed bulk RNA sequencing on HRR-proficient MyC-CaP cells treated with PARPi Olaparib or control vehicle.
Pathway enrichment analysis revealed a marked upregulation of CD73 (NT5E), an emerging immune checkpoint ectoenzyme that generates extracellular adenosine, suggesting an adaptive mechanism that undermines PARPi efficacy and enables unwanted immunosuppression. CD73 induction by PARPi was confirmed in both human and mouse prostate cancer cell lines, with more pronounced effects in the HRR-compromised PTEN knock-out (KO) cells.
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Mechanistically, Olaparib-driven CD73 expression was mediated through the DNA damage-activated ATR-CHEK1-IRF1 and TGF-β1-ΑΚΤ signaling pathways. Concurrently, PARPi enhanced tumor cell immunogenicity by activating the type I interferon pathway and antigen presentation machinery. In vivo, combining Olaparib with CD73 blockade therapy delayed tumor growth, improved T-cell infiltration, and augmented antigen-specific CD8⁺ T-cell effector function across HRR-proficient and PTEN KO prostate cancer models.
These findings highlight PARPi-induced CD73 upregulation as a novel resistance mechanism and support PARPi plus CD73 blockade as a promising therapeutic strategy for mCRPC, irrespective of HRR status.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312794 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312794 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1377422 ncbi.nlm.nih.gov/bioproject/PRJNA1377422 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · RNA sequencing 75% · Sequencing 75%
Related
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE312794 | 15 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[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:10090 | 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 |