Abstract
BackgroundTumour 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).MethodsWe 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.ResultsHigh 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.ConclusionJAG2+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.
Highlights
Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies
Tumour associated neutrophils correlate with poor clinical outcomes in epithelial ovarian cancer (EOC) To elucidate the influence of TANs on clinical outcomes, we performed immunohistochemical analysis of CD66b in tissue microarray (TMA) and quantified (Supplementary Fig. 1)
Due to the limited number of endometrioid and mucinous ovarian cancer, we further investigated the clinical significance of TAN in serous and clear cell ovarian cancer patients
Summary
Tumour associated neutrophils (TANs) play a controversial role in regulating immune surveillance and immune evasion in various malignancies. We investigated the relevance of TANs with the prognosis and immune microenvironment of epithelial ovarian cancer (EOC). We explored the therapeutic merit of targeting Notch signalling in EOC and determined its involvement in the immune microenvironment. 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. 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. Cancer immunotherapy has achieved unprecedented success in a large number of patients with multiple cancers and is conducting EOC testing.[3] Clinical trials of immunotherapy (such as Keytruda, Opdivo, and Aavelumab)[4] have produced ~10–15% relief in patients with advanced and recurrent EOC, and sometimes transient remission.[5] Taken together, the relatively low response rate of immune checkpoint inhibitors warrant further investigation of the molecular and cellular mechanisms of EOC immune evasion
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