J Gynecol Oncol.  2023 May;34(3):e25. 10.3802/jgo.2023.34.e25.

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor

• Nakamura T
• Kajihara N
• Hama N
• Kobayashi T
• Otsuka R
• Han N
• Wada H
• Hasegawa Y
• Suzuki N
• Seino Ki

• KMID: 2552561
• DOI: http://doi.org/10.3802/jgo.2023.34.e25

Abstract

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.

Keyword

Interleukin-34; BRCA1-Associated Cancer; PARP Inhibitor; Therapeutic Resistance; XCR1⁺ Dendritic Cell; CD8⁺ T Cell