Int J Biol Sci 2023; 19(6):1846-1860. doi:10.7150/ijbs.79654 This issue Cite

Research Paper

Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer

Dong Yang#1, Fu-Xue Huang#1,3, Wei Wei#1,2, Qia-Qia Li#1,2, Jun-Wan Wu1, Yun Huang1,4, Zhi-Ling Li1, Hai-Liang Zhang1, Xuan Li1, Qiu-Er Yuan2, Qing-shan Chen1, Gong-kan Feng1, Deng Rong1✉, Jun-Dong Li1,2✉, Xiao-Feng Zhu1✉

1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
2. Department of Gynecological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
3. Department of Radiation Oncology & Therapy, Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China.
4. Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
# Dong Yang, Fu-Xue Huang, Wei Wei, Qia-Qia Li contributed equally to this article.

Citation:
Yang D, Huang FX, Wei W, Li QQ, Wu JW, Huang Y, Li ZL, Zhang HL, Li X, Yuan QE, Chen Qs, Feng Gk, Rong D, Li JD, Zhu XF. Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer. Int J Biol Sci 2023; 19(6):1846-1860. doi:10.7150/ijbs.79654. https://www.ijbs.com/v19p1846.htm
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Abstract

Graphic abstract

In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined in vitro and in vivo. The decision tree plotted on the basis of HRD and HRD-EXCUTE indicated the HRD patients without the HRD functional phenotype were largely unresponsive to immunotherapy, which was validated by the immunotherapeutic cohorts. Furthermore, loss of HRD-EXCUTE in the HRD patients attenuated immunogenicity and inhibited immune cells in tumor microenvironment. Moreover, Niraparib combined with Entinostat induced HRD-EXCUTE by activating the cGAS-STING pathway and increasing the histone acetylation. The combination therapy could enhance the cytotoxicity of immune cells, and promote pro-immune cells infiltrating into ascites, resulting in inhibited ovarian cancer growth. The HRD functional phenotype HRD-EXCUTE was set up as a potent biomarker to identify whether HRD patients can benefit from immunotherapy. Loss of HRD-EXCUTE in HRD patients were largely insensitive to immunotherapy. The combination of PARPi with HDACi could improve the efficacy of the PARPi-based immunotherapy in ovarian cancer by augmenting the HRD functional phenotype.

Keywords: Ovarian cancer, Homologous recombination deficiency, Transcriptomic functional Phenotype, Immunotherapy


Citation styles

APA
Yang, D., Huang, F.X., Wei, W., Li, Q.Q., Wu, J.W., Huang, Y., Li, Z.L., Zhang, H.L., Li, X., Yuan, Q.E., Chen, Q.s., Feng, G.k., Rong, D., Li, J.D., Zhu, X.F. (2023). Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer. International Journal of Biological Sciences, 19(6), 1846-1860. https://doi.org/10.7150/ijbs.79654.

ACS
Yang, D.; Huang, F.X.; Wei, W.; Li, Q.Q.; Wu, J.W.; Huang, Y.; Li, Z.L.; Zhang, H.L.; Li, X.; Yuan, Q.E.; Chen, Q.s.; Feng, G.k.; Rong, D.; Li, J.D.; Zhu, X.F. Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer. Int. J. Biol. Sci. 2023, 19 (6), 1846-1860. DOI: 10.7150/ijbs.79654.

NLM
Yang D, Huang FX, Wei W, Li QQ, Wu JW, Huang Y, Li ZL, Zhang HL, Li X, Yuan QE, Chen Qs, Feng Gk, Rong D, Li JD, Zhu XF. Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer. Int J Biol Sci 2023; 19(6):1846-1860. doi:10.7150/ijbs.79654. https://www.ijbs.com/v19p1846.htm

CSE
Yang D, Huang FX, Wei W, Li QQ, Wu JW, Huang Y, Li ZL, Zhang HL, Li X, Yuan QE, Chen Qs, Feng Gk, Rong D, Li JD, Zhu XF. 2023. Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer. Int J Biol Sci. 19(6):1846-1860.

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