CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer.
We recently established that high STAT1 expression and associated T helper type I tumour immune microenvironment (TME) are prognostic and chemotherapy response predictive biomarkers in high-grade serous ovarian cancer (HGSC). STAT1 induced chemokine CXCL10 is key to the recruitment of lymphocytes in the TME and is significantly highly expressed in the tumours from patients with longer survival. In the current study we therefore aimed to elucidate the role CXCL10 in disease progression and tumour immune transcriptomic alterations using the ID8 syngeneic murine model of HGSC.



ID8 ovarian cancer cells were engineered for stable knockdown (KD) and overexpression (OX) of CXCL10. The OX and KD cell line derivatives, along with their respective vector controls, were implanted in immunocompetent C57BL/6 mice via intra-peritoneal injections. At end point, immune transcriptomic profiling of tumour tissues and multiplex cytokine profiling of ascites, was performed. Effect of CXCL10 expression on the tumour vasculature and tumour cell proliferation was evaluated by CD31 and Ki67 immunostaining, respectively.



Increased CXCL10 expression led to decreased tumour burden and malignant ascites accumulation in the ID8 syngeneic murine model of HGSC. The ascites levels of IL-6 and VEGF were significantly reduced in OX mice compared to the vector controls. The OX tumours also showed reduced vasculature (CD31) and proliferative index (Ki67) compared to the control tumours. Significantly higher expression of genes associated with antigen processing, apoptosis and T cell function was observed in OX tumours compared to the controls. Reduced CXCL10 expression in tumours from KD mice led to increased ascites accumulation and disease progression compared to the controls.



CXCL10 is a positive determinant of anti-tumour immune responses in HGSC TME and disease progression. These findings are foundational for future translational studies aimed at improving treatment response and survival in HGSC patients, via exploiting the TME.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Katrina
K
K Au
Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Nichole
N
Peterson
Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Peter
P
Truesdell
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Gillian
G
Reid-Schachter
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Kasra
K
Khalaj
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Runhan
R
Ren
Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Julie-Ann
JA
Francis
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Charles H
CH
Graham
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada; Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Andrew W
AW
Craig
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada; Department of Obstetrics and Gynecology, Queen's University, Kingston, Ontario K7L 3N6, Canada; Cancer Biology and Genetics Division, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: kotim@queensu.ca.
Madhuri
M
Koti
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000276:immunology*
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse
CXCL10; ID8; Interferon; Ovarian cancer; Tumour immune microenvironment