The Tumor Microenvironment of Clear-Cell Ovarian Cancer

Some patients with advanced clear-cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from 45 patients, 9 with Federation Interna-tionale des Gynaecologistes et Obstetristes (FIGO) stage I/II (early CCOC) and 36 with FIGO stage III/IV (advanced CCOC). We investigated 14 immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray data set from a second cohort of 29 patients and compared the TMEs of ARID1A-wildtype (ARID1A(wt)) versus ARID1A-mutant (ARID1A(mut)) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138(+) plasma cells, the LE had more CD20(+) B cells and T cells, whereas the stroma had more mast cells and alpha SMA(+) fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared with early CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating "TGF beta remodeling of the extracellular matrix" as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1A(wt) and ARID1A(mut) CCOC, which may refiect different paths of tumori-genesis and the relationship to endometriosis. Increased infiltration of CD8(+) T cells within the MCA and CD4(+) T cells at the LE and stroma significantly associated with decreased overall survival.