Deficiency of tumor-expressed B7-H3 augments anti-tumor efficacy of anti-PD-L1 monotherapy rather than the combined chemoimmunotherapy in ovarian cancer

• Published in: Pharmacological research 2022-12, Vol.186, p.106512-106512, Article 106512
• Main Authors: Huang, Mingyan, Luo, Jianhua, Ji, Xinpei, Hu, Miao, Xue, Yiquan, Liu, Qiuyan
• Format: Article
• Language: English
• Subjects: Animals; Anti-PD-L1; B7 Antigens - metabolism; B7-H3; Chemoimmunotherapy; Female; Humans; Immunotherapy; Mice; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Paclitaxel; Paclitaxel - pharmacology; Paclitaxel - therapeutic use; Tumor Microenvironment
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2022.106512

As a high mortality gynecological malignancy, most ovarian cancer patients experience refractory to standard chemotherapy, current immunotherapy or chemoimmunotherapy in clinic and clinical trials. The underlying mechanisms and biomarkers predictive of response for patient selection is quite urgent. In this study, we found that the level of tumor-expressed B7-H3 is positively correlated with the poorer prognosis in ovarian cancer patients. Therapeutically, in syngeneic mouse model of ovarian cancer, deficiency of tumor-expressed B7-H3 significantly potentiates the anti-tumor efficacy of paclitaxel or PD-L1 blockade monotherapy. However, combination of paclitaxel plus anti-PD-L1 has no synergistic effects than PD-L1 blockade monotherapy. Mechanistically, deficiency of tumor-expressed B7-H3 attenuates inflammatory cytokine IL-6 production, upregulates type I interferon (IFN) expression and increases paclitaxel-induced tumor cells apoptosis via caspase 3 activation pathway, resulting in reprogramming the tumor microenvironment including increasing the infiltration of effector T lymphocytes and decreasing the recruitment of Ly6G+CD11b+ myeloid-derived suppressor cells (MDSCs) in vivo. Collectively, these results demonstrate that deficiency of tumor-expressed B7-H3 enhances the anti-tumor efficacy of paclitaxel or PD-L1 blockade monotherapy rather than their combined chemoimmunotherapy in ovarian cancer, suggesting that B7-H3 may be a potential predictive biomarker for beneficial patient stratification and a candidate therapeutic target in ovarian cancer. [Display omitted]