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

Stefanie Seitz, Tobias F. Dreyer, Christoph Stange, Katja Steiger, Rosalinde Bräuer, Leandra Scheutz, Gabriele Multhoff, Wilko Weichert, Marion Kiechle, Viktor Magdolen, Holger Bronger

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

32 Zitate (Scopus)

Abstract

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−/− 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. 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.

OriginalspracheEnglisch
Seiten (von - bis)1470-1480
Seitenumfang11
FachzeitschriftBritish Journal of Cancer
Jahrgang126
Ausgabenummer10
DOIs
PublikationsstatusVeröffentlicht - 1 Juni 2022

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