Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds

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 (HTS2) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature distinguishing cold tumors from hottumors. 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 CXCL10 and CXCL11 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.

Automated summary

Combination immunotherapy using AKIs has been found to reprogram TIP gene expression, promote T cell infiltration in TNBC, and enhance the efficacy of PD-1, suggesting a novel strategy for discovering combination immunotherapy compounds.