CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer.

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. Impact of Cxcl9 overexpression in the murine ID8-Trp53-/- and ID8-Trp53-/-Brca2-/- 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. 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. 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. © 2022. The Author(s).

Citation

Stefanie Seitz, Tobias F Dreyer, Christoph Stange, Katja Steiger, Rosalinde Bräuer, Leandra Scheutz, Gabriele Multhoff, Wilko Weichert, Marion Kiechle, Viktor Magdolen, Holger Bronger. CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer. British journal of cancer. 2022 Jun;126(10):1470-1480

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PMID: 35314795

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