Oncolytic vesicular stomatitis virus alone or in combination with JAK inhibitors is effective against ovarian cancer.

Therapy-resistant ovarian cancers have a poor prognosis and novel effective treatment options are urgently needed. In this study, we evaluated the therapeutic efficacy of the oncolytic vesicular stomatitis virus (VSV) against a panel of patient-derived ovarian cancer cell lines of all epithelial subtypes. Notably, we found that most of the cell lines were sensitive to VSV virotherapy. With the objective of improving treatment efficacy for the oncolytic virus-resistant cell lines, we tested various combinations with ovarian cancer standard of care drugs: olaparib, carboplatin, paclitaxel, doxorubicin, cyclophosphamide, and gemcitabine. While none of these combinations revealed to be beneficial, further experiments demonstrated that the antiviral interferon pathway was functional in VSV-resistant cell lines. Given that interferons signal through Janus kinase (JAK)-STAT to mediate their antiviral function, we tested combinations of oncolytic VSV with clinically relevant JAK inhibitors. Our results show that combining VSV with various JAK inhibitors, including ruxolitinib, enhances VSV virotherapy and treatment efficacy. Altogether, we show that VSV, either as a stand-alone treatment or in combination with JAK inhibitors provides an effective therapeutic option for ovarian cancer patients.

Increased expression of the immunoproteasome subunits PSMB8 and PSMB9 by cancer cells correlate with better outcomes for triple-negative breast cancers.

Proteasome dependency is a feature of many cancers that can be targeted by proteasome inhibitors. For some cancer types, notably breast cancer and triple-negative breast cancer (TNBC), high mRNA expression of a modified form of the proteasome, called the immunoproteasome (ImP), correlates with better outcomes and higher expression of one ImP subunit was associated with slower tumor growth in a small patient cohort. While these findings are in line with an anti-tumoral role of the ImP in breast cancer, studies investigating ImP expression at the protein level in large patient cohorts are lacking. Furthermore, while ImPs can be found in both immune and non-immune cells, the cellular source is often ignored in correlative studies. In order to determine the impact of ImP expression on breast cancer outcomes, we assessed the protein expression and cellular source of the ImP subunits PSMB8 and PSMB9 in a cohort of 2070 patients. Our data show a clear correlation between high ImP expression and better outcomes, most notably for TNBC patients and when tumor cells rather than stromal or immune cells express PSMB8 or PSMB9. Our results therefore suggest that ImP expression by tumor cells could be used as prognostic markers of TNBC outcomes.

Negative Regulation of Zap70 by Lck Forms the Mechanistic Basis of Differential Expression in CD4 and CD8 T Cells.

Lck and Zap70, two non-receptor tyrosine kinases, play a crucial role in the regulation of membrane proximal TCR signaling critical for thymic selection, CD4/CD8 lineage choice and mature T cell function. Signal initiation upon TCR/CD3 and peptide/MHC interaction induces Lck-mediated phosphorylation of CD3 ITAMs. This is necessary for Zap70 recruitment and its phosphorylation by Lck leading to full Zap70 activation. In its native state Zap70 maintains a closed conformation creating an auto-inhibitory loop, which is relieved by Lck-mediated phosphorylation of Y315/Y319. Zap70 is differentially expressed in thymic subsets and mature T cells with CD8 T cells expressing the highest amount compared to CD4 T cells. However, the mechanistic basis of differential Zap70 expression in thymic subsets and mature T cells is not well understood. Here, we show that Zap70 is degraded relatively faster in DP and mature CD4 T cells compared to CD8 T cells, and inversely correlated with relative level of activated Zap70. Importantly, we found that Zap70 expression is negatively regulated by Lck activity: augmented Lck activity resulting in severe diminution in total Zap70. Moreover, Lck-mediated phosphorylation of Y315/Y319 was essential for Zap70 degradation. Together, these data shed light on the underlying mechanism of Lck-mediated differential modulation of Zap70 expression in thymic subsets and mature T cells.