Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33523948.
- Also identified by DOI 10.1126/sciadv.abd7851 and PMC identifier 10964968.
- Licence recorded as CC BY-NC.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Combination immunotherapy is promising to overcome the limited objective response rates of immune checkpoint blockade (ICB) therapy. Here, a tumor immunological phenotype (TIP) gene signature and high-throughput sequencing-based high-throughput screening (HTS<sup>2</sup>) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature distinguishing "cold" tumors from "hot" tumors. After screening thousands of compounds, we identified that aurora kinase inhibitors (AKIs) could reprogram the expression pattern of TIP genes in triple-negative breast cancer (TNBC) cells. AKIs treatments up-regulate expression of chemokine genes <i>CXCL10</i> and <i>CXCL11</i> through inhibiting aurora kinase A (AURKA)-signal transducer and activator of transcription 3 (STAT3) signaling pathway, which promotes effective T cells infiltrating into tumor microenvironment and improves anti-programmed cell death 1 (PD-1) efficacy in preclinical models. Our study established a novel strategy to discover combination immunotherapy compounds and suggested the therapeutic potential of combining AKIs with ICB for the treatment of TNBC.