Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer

Abstract

Background

Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies. Here, we investigated the relevance of TANs with the prognosis and immune microenvironment of epithelial ovarian cancer (EOC).

Methods

We characterised TANs using flow cytometric analysis and immunofluorescence analysis. The prognostic merit of TANs in EOC was evaluated using cox regression analysis. Furthermore, we explored the therapeutic merit of targeting Notch signalling in EOC and determined its involvement in the immune microenvironment.

Results

High level of TANs is associated with a dismal prognosis and immune tolerance in EOC. TANs impaired cytotoxic effects of CD8 ⁺ T cells partly through Jagged2 (JAG2). Notch pathway blocked using γ-secretase inhibitor LY3039478 and anti-JAG2 antibody led to retarded tumour growth and augmented cytotoxic effects of CD8 ⁺ T cells. IL-8 contributes to the recruitment of TANs and the induction of JAG2 expression in TANs. Blockade of CXCR2 signalling reduces tumour growth rate, accompanied by a decreasing amount of TANs and increasing activity of CD8 ⁺ T cells. JAG2 ⁺TANs is an independent predictor of clinical outcomes.

Conclusion

JAG2 ⁺TANs are closely linked to IL-8-driven immune evasion microenvironment and may serve as a promising therapeutic target for the reinvigoration of anti-tumour immunity.