CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patientes atteintes d'un cancer de l'ovaire, cette étude met en évidence le rôle de la chimiokine CXCL9 dans l'inhibition de la croissance tumorale et la réponse aux inhibiteurs de points de contrôle immunitaire
Background : Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied. Methods : Impact of Cxcl9 overexpression in the murine ID8-Trp53
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and ID8-Trp53
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ovarian cancer models on survival, cellular immune composition, PD-L1 expression and anti-PD-L1 therapy. CXCL9 expression analysis in ovarian cancer subtypes and correlation to reported ICB response. Results : CXCL9 overexpression resulted in T-cell accumulation, delayed ascites formation and improved survival, which was dependent on adaptive immune function. In the ICB-resistant mouse model, the chemokine was sufficient to enable a successful anti-PD-L1 therapy. In contrast, these effects were abrogated in Brca2-deficient tumours, most likely due to an already high intrinsic chemokine expression. Finally, in ovarian cancer patients, the clear-cell subtype, known to respond best to ICB, displayed a significantly higher proportion of CXCL9high tumours than the other subtypes. Conclusions : CXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity.