학술논문
Profiling the immune landscape in mucinous ovarian carcinoma.
Document Type
article
Author
Meagher, Nicola; Hamilton, Phineas; Milne, Katy; Thornton, Shelby; Harris, Bronwyn; Weir, Ashley; Alsop, Jennifer; Bisinoto, Christiani; Brenton, James; Brooks-Wilson, Angela; Chiu, Derek; Cushing-Haugen, Kara; Fereday, Sian; Garsed, Dale; Gayther, Simon; Gentry-Maharaj, Aleksandra; Gilks, Blake; Jimenez-Linan, Mercedes; Kennedy, Catherine; Le, Nhu; Piskorz, Anna; Riggan, Marjorie; Shah, Mitul; Singh, Naveena; Talhouk, Aline; Widschwendter, Martin; Bowtell, David; Candido Dos Reis, Francisco; Cook, Linda; Fortner, Renée; García, María; Harris, Holly; Huntsman, David; Köbel, Martin; Menon, Usha; Pharoah, Paul; Doherty, Jennifer; Anglesio, Michael; Pike, Malcolm; Pearce, Celeste; Friedlander, Michael; DeFazio, Anna; Nelson, Brad; Ramus, Susan; Karnezis, Anthony
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Subject
Language
Abstract
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically cold, suggesting they may have limited response to current immunotherapies.