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Macrophage-derived CCL23 upregulates expression of T-cell exhaustion markers in ovarian cancer.
Kamat, Kalika; Krishnan, Venkatesh; Dorigo, Oliver.
Afiliación
  • Kamat K; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford Women's Cancer Center, Stanford Cancer Institute, Stanford, CA, USA.
  • Krishnan V; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford Women's Cancer Center, Stanford Cancer Institute, Stanford, CA, USA.
  • Dorigo O; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford Women's Cancer Center, Stanford Cancer Institute, Stanford, CA, USA. odorigo@stanford.edu.
Br J Cancer ; 127(6): 1026-1033, 2022 10.
Article en En | MEDLINE | ID: mdl-35750747
BACKGROUND: Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23 (CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 (CCR1). However, the effect of CCL23 on other immune cells in the TME is unknown. METHODS: CCL23 levels were measured by ELISA. The expression of surface markers in exhaustion assays was quantified by flow cytometry. Signalling pathways were identified by phosphokinase array and validated by western blot. RESULTS: Ascites from patients with high-grade serous ovarian cancer (HGSC) contain high levels of CCL23. Similarly, significantly higher CCL23 levels were found in plasma from HGSC patients compared to healthy individuals. RNA-seq analysis of ovarian cancer tissues from TCGA showed that expression of CCL23 correlated with the presence of macrophages. In tissues with high levels of CCL23 and macrophage content, the fraction of CD8 + T cells expressing exhaustion markers CTLA-4 and PD-1 were significantly higher compared to low-level CCL23 tissues. In vitro, CCL23 induced upregulation of immune checkpoint proteins on CD8 + T cells, including CTLA-4, TIGIT, TIM-3 and LAG-3 via phosphorylation of GSK3ß in CD8 + T cells. CONCLUSIONS: Our data suggest that CCL23 produced by macrophages contributes to the immune-suppressive TME in ovarian cancer by inducing an exhausted T-cell phenotype.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Quimiocinas CC / Microambiente Tumoral / Macrófagos Límite: Female / Humans Idioma: En Revista: Br J Cancer Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Quimiocinas CC / Microambiente Tumoral / Macrófagos Límite: Female / Humans Idioma: En Revista: Br J Cancer Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos