The putative effects of carboplatin based neoadjuvant chemotherapy on tumor microenvironment of epithelial ovarian carcinoma

Abstract

Abstract For late-stage epithelial ovarian carcinoma (EOC) patients, carboplatin based neoadjuvant chemotherapy (NACT) followed interval debulking surgery (IDS) could be alternative choice. The failure of immune checkpoint inhibitors combining chemotherapy for EOC patients promote us to comprehensively understand the impact of NACT on the tumor mircroenvironment (TME) of EOC. Methods: The RNA-sequencing profiles of EOC patients before and after NACT were downloaded from the Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) were calculated and further analyzed using GO and KEGG analyses. The variation of immune cell infiltration upon NACT was analyzed by CIBERSORT and further identified using immunohistochemistry and multi-immunofluorescence assays. Results: A total of 6 GEO datasets were included in our study, and 1138 DEGs were found compared the pre-NACT with post-NACT groups. The inflammation-related IL-17 signaling pathway and the apoptosis-related P53 signaling pathway were the most enriched signaling pathways in post-NACT tissues. A diagnostic pattern using the 6 hub genes, figured out by protein network analysis, could efficiently distinguish the normal ovarian tissues from the gynecology malignancies, including OC. Upon NACT, the phenotype of immune cells in the TME was more complex. Infiltrating follicular helper T (Tfh) cells and M1 macrophages significantly decreased, while the proportion of resting NK cells significantly increased. Although total M2 macrophages did not change significantly, the morphology and phenotype of relative macrophages changed, especially the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) + macrophages. LYVE1 + macrophages co-expressed with CD206 but not CD68+, and they formed multicellular “nest” structures in the stroma, which might be related to chemotherapy sensitivity of EOC. Conclusion: The alterations in the TME of EOC following NACT exposure were complex and dynamic. Not only the tumor cells, but also immunological factors are involved in mediating the chemotherapeutic response. The LYVE1 + CD206 + perivascular TAMs were identified in EOC patients, and this specific subtype TAMs might be correlated with chemotherapeutic response, which will allow for the future development of novel immunologic therapies to combat chemoresistance.