👤 Kris Van Moer

The release of CCL5 and CXCL10 is essential for recruiting cytotoxic immune cells into the tumor microenvironment and enhancing the efficacy of cancer immunotherapy. Type I IFNs, particularly IFNβ, activate signaling pathways that induce the expression of these chemokines. In our recent study, we explored the impact and underlying mechanisms of inhibiting the kinase activity of VPS34, a key lipid kinase in the autophagy/endosomal trafficking system, on the expression of CCL5 and CXCL10 in preclinical cancer mouse models. Using NanoString gene expression technology, we analyzed tumors from mice treated with the VPS34 inhibitor SB02024 and demonstrated that the expression of CCL5 and CXCL10 is increased through a cGAS-STING-dependent mechanism within cancer cells. CCL5 (C-C motif chemokine 5); CXCL10 (C-X-C motif chemokine 10); IFN (interferon); VPS34 (vacuolar protein sorting 34); cGAS (cyclic GMP-AMP Synthase); STING (stimulator of interferon genes protein); cGAMP (2'3'-cyclic guanosine monophosphate-adenosine monophosphate). Show less

We have recently demonstrated that inhibiting VPS34 enhances T-cell-recruiting chemokines through the activation of the cGAS/STING pathway using the STING agonist ADU-S100. Combining VPS34 inhibitors with ADU-S100 increased cytokine release and improved tumor control in mouse models, suggesting a potential synergy between VPS34 inhibition and therapies based on STING agonists. Show less

Triple-negative subtype of breast cancer (TNBC) is hallmarked by frequent disease relapse and shows highest mortality rate. Although PD-1/PD-L1 immune checkpoint blockades have recently shown promising clinical benefits, the overall response rate remains largely insufficient. Hence, alternative therapeutic approaches are warranted. Given the immunosuppressive properties of CD73-mediated adenosine release, CD73 blocking approaches are emerging as attractive strategies in cancer immunotherapy. Understanding the precise mechanism regulating the expression of CD73 is required to develop effective anti-CD73-based therapy. Our previous observations demonstrate that the transcription factors driving epithelial-to-mesenchymal transition (EMT-TF) can regulate the expression of several inhibitory immune checkpoints. Here we analyzed the role of the EMT-TF SNAI1 in the regulation of CD73 in TNBC cells. We found that doxycycline-driven SNAI1 expression in the epithelial -like TNBC cell line MDA-MB-468 results in CD73 upregulation by direct binding to the CD73 proximal promoter. SNAI1-dependent upregulation of CD73 leads to increased production and release of extracellular adenosine by TNBC cells and contributes to the enhancement of TNBC immunosuppressive properties. Our data are validated in TNBC samples by showing a positive correlation between the mRNA expression of CD73 and SNAI1. Overall, our results reveal a new CD73 regulation mechanism in TNBC that participates in TNBC-mediated immunosuppression and paves the way for developing new treatment opportunities for CD73-positive TNBC. Show less

CMTM6 is a critical regulator of cell surface expression of PD-L1 in tumor cells, but little is known about the transcriptional regulation of CMTM6. Here we report that the expression of CMTM6 positively correlates with the epithelial to mesenchymal transition (EMT) score in breast cancer cell lines and with the major EMT marker Vimentin in triple-negative breast cancers (TNBC). We showed that CMTM6 is concomitantly overexpressed with PD-L1 in breast mesenchymal compared with the epithelial cells. Driving a mesenchymal phenotype in SNAI1-inducible MCF-7 cells (MCF-7 Show less