Profiling the immune landscape in mucinous ovarian carcinoma
Nicola S. Meagher, Phineas T. Hamilton, Katy Milne, Shelby Thornton, Bronwyn Harris, Ashley Weir, Jennifer Alsop, Christiani Bisinoto, James D. Brenton, Angela Brooks‐Wilson, Derek S. Chiu, Kara L. Cushing‐Haugen, Sián Fereday, Dale W. Garsed, Simon A. Gayther, Aleksandra Gentry‐Maharaj, C. Blake Gilks, Mercedes Jimenez‐Liñan, Catherine J. Kennedy, Nhu D. Le, Anna Piskorz, Marjorie J. Riggan, Mitul Shah, Naveena Singh, Aline Talhouk, Martin Widschwendter, David D.L. Bowtell, Francisco José Cândido dos Reis, Linda S. Cook, Renée T. Fortner, María J. García, Holly R. Harris, David G. Huntsman, Anthony N. Karnezis, Martin Köbel, Usha Menon, Paul D.P. Pharoah, Jennifer A. Doherty, Michael S. Anglesio, Malcolm C. Pike, Celeste Leigh Pearce, Michael Friedländer, Anna DeFazio, Brad H. Nelson, Susan J. Ramus
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.