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KMID : 1137020230340030025
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Journal of Gynecologic Oncology
2023 Volume.34 No. 3 p.25 ~ p.25
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Interleukin-34 cancels anti-tumor immunity by PARP inhibitor
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Takayoshi Nakamura
Nabeel Kajihara
Naoki Hama
Takuto Kobayashi
Ryo Otsuka
Nanumi Han
Haruka Wada
Yoshinori Hasegawa
Nao Suzuki
Ken-ichiro Seino
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Abstract
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Objective: Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME).
Methods: In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34.
Results: We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34.
Conclusion: These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.
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KEYWORD
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Interleukin-34, BRCA1-Associated Cancer, PARP Inhibitor, Therapeutic Resistance, XCR1+ Dendritic Cell, CD8+ T Cell
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