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Interleukin-34 cancels anti-tumor immunity by PARP inhibitor
Takayoshi Nakamura1,2, Nabeel Kajihara1, Naoki Hama1
1Division of Immunobiology, Graduate School of Medicine, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
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.
Insights
Interleukin-34 (IL-34) drives therapeutic resistance in ovarian cancer by suppressing anti-tumor immunity. Targeting IL-34 may overcome resistance to poly (ADP-ribose) polymerase (PARP) inhibitors, improving patient survival.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors improve progression-free survival in BRCA1-associated ovarian cancer but therapeutic resistance eventually develops.
- Interleukin-34 (IL-34) is a poor prognostic factor in several cancers, including ovarian cancer, and contributes to chemotherapy resistance.
- IL-34's role in PARP inhibitor resistance, potentially via tumor microenvironment (TME) modulation, requires investigation.
Purpose of the Study:
- To evaluate IL-34 as a prognostic factor in ovarian serous carcinoma.
- To investigate the impact of IL-34 on the efficacy of PARP inhibitor therapy in BRCA1-associated ovarian cancer.
- To elucidate the mechanism by which IL-34 confers PARP inhibitor resistance.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) data for IL-34 expression and prognosis in ovarian serous carcinoma.
- Utilizing CRISPR-Cas9 genome editing in a mouse model to assess PARP inhibitor efficacy with and without IL-34.
- Investigating the role of the XCR1+ DC-CD8+ T cell axis in mediating anti-tumor immunity.
Main Results:
- High IL34 expression is an independent poor prognostic factor in ovarian serous carcinoma, correlating with shorter overall survival.
- PARP inhibitor therapy enhances anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis in BRCA1-associated ovarian cancer.
- The presence of IL-34 abrogates the anti-tumor immune response induced by PARP inhibitors.
Conclusions:
- Tumor-derived IL-34 promotes an immunosuppressive TME, leading to PARP inhibitor therapeutic resistance.
- IL-34 plays a critical pathological role in ovarian cancer progression and resistance.
- IL-34 represents a potential therapeutic target to overcome PARP inhibitor resistance in ovarian cancer.
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