Xiaofan Lu1,2, Caoyu Ji1,2, Liyun Jiang1,2,3, Yue Zhu1,2, Yujie Zhou4, Jialin Meng5,6,7, Jun Gao1,2, Tao Lu1, Junmei Ye1, Fangrong Yan1,2. 1. State Key laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. 2. Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China. 3. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Texas, USA. 4. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China. 5. Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. 6. Institute of Urology & Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China. 7. Department of Urology, University of Rochester Medical Center, Rochester, NY, USA.
Abstract
OBJECTIVE: Due to limited immunological profiles of high-grade serous ovarian cancer (HGSOC), we aimed to characterize its molecular features to determine whether a specific subset that can respond to immunotherapy exists. MATERIALS AND METHODS: A training cohort of 418 HGSOC samples from TCGA was analysed by consensus non-negative matrix factorization. We correlated the expression patterns with the presence of immune cell infiltrates, immune regulatory molecules and other genomic or epigenetic features. Two independent cohorts containing 482 HGSOCs and in vitro experiments were used for validation. RESULTS: We identified immune and non-immune groups where the former was enriched in signatures that reflect immune cells, infiltration and PD-1 signalling (all, P < 0.001), and presented with a lower chromosomal aberrations but increased neoantigens, tumour mutation burden, and microsatellite instability (all, P < 0.05); this group was further refined into two microenvironment-based subtypes characterized by either immunoactivation or carcinoma-associated fibroblasts (CAFs) and distinct prognosis. CAFs-immune subtype was enriched for factors that mediate immunosuppression and promote tumour progression, including highly expressed stromal signature, TGF-β signalling, epithelial-mesenchymal transition and tumour-associated M2-polarized macrophages (all, P < 0.001). Robustness of these immune-specific subtypes was verified in validation cohorts, and in vitro experiments indicated that activated-immune subtype may benefit from anti-PD1 antibody therapy (P < 0.05). CONCLUSION: Our findings revealed two immune subtypes with different responses to immunotherapy and indicated that some HGSOCs may be susceptible to immunotherapies or combination therapies.
OBJECTIVE: Due to limited immunological profiles of high-grade serous ovarian cancer (HGSOC), we aimed to characterize its molecular features to determine whether a specific subset that can respond to immunotherapy exists. MATERIALS AND METHODS: A training cohort of 418 HGSOC samples from TCGA was analysed by consensus non-negative matrix factorization. We correlated the expression patterns with the presence of immune cell infiltrates, immune regulatory molecules and other genomic or epigenetic features. Two independent cohorts containing 482 HGSOCs and in vitro experiments were used for validation. RESULTS: We identified immune and non-immune groups where the former was enriched in signatures that reflect immune cells, infiltration and PD-1 signalling (all, P < 0.001), and presented with a lower chromosomal aberrations but increased neoantigens, tumour mutation burden, and microsatellite instability (all, P < 0.05); this group was further refined into two microenvironment-based subtypes characterized by either immunoactivation or carcinoma-associated fibroblasts (CAFs) and distinct prognosis. CAFs-immune subtype was enriched for factors that mediate immunosuppression and promote tumour progression, including highly expressed stromal signature, TGF-β signalling, epithelial-mesenchymal transition and tumour-associated M2-polarized macrophages (all, P < 0.001). Robustness of these immune-specific subtypes was verified in validation cohorts, and in vitro experiments indicated that activated-immune subtype may benefit from anti-PD1 antibody therapy (P < 0.05). CONCLUSION: Our findings revealed two immune subtypes with different responses to immunotherapy and indicated that some HGSOCs may be susceptible to immunotherapies or combination therapies.