Cancers, Vol. 13, Pages 3733: Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression

Cancers, Vol. 13, Pages 3733: Targeting Replication Stress Using CHK1 Inhibitor Promotes Innate and NKT Cell Immune Responses and Tumour Regression Cancers doi: 10.3390/cancers13153733 Authors: Martina Proctor Jazmina L. Gonzalez Cruz Sheena M. Daignault-Mill Margaret Veitch Bijun Zeng Anna Ehmann Muhammed Sabdia Cameron Snell Colm Keane Riccardo Dolcetti Nikolas K. Haass James W. Wells Brian Gabrielli Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8+ T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4+ Treg and FoxP3+ NKT cells. The number of these accumulated during treatment, the increase in FoxP3+ NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effe...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research