dianas 9(1) > Lodewijk etal

dianas | Vol 9 Num 1 | marzo 2020 | e202003a02

Prognostic and predictive immune gene signatures and correlation with homologous recombination deficiency in high grade serous ovarian cancer.

Iris Lodewijk^a, Marta Dueñas, Cristian Suarez-Cabrera, Rosa García-Martin, Luis Manso, Jesús M Paramio

Fundación de Investigación Hospital 12 de Octubre/CIEMAT.

a. irisadriana.lodewijk@externos.ciemat.es

V Congreso de Señalización Celular, SECUAH 2020.
16-18 de marzo, 2020. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: Ovarian Cancer; Immune gene signatures; Homologous recombination deficiency; Immunotherapy

Abstract

High grade serous ovarian cancer (HGSOC) is an inherently aggressive malignancy, which commonly presents as advanced-stage disease and accounts for the majority of ovarian cancer deaths. Primary debulking surgery followed by chemotherapy represents standard treatment of HGSOC patients, whereas patients who have unresectable disease or represent poor surgical candidates are subject to neoadjuvant chemotherapy (NACT). Genetic and epigenetic alterations in genes of the homologous recombination (HR) DNA repair pathway have been found in approximately 50% of HGSOCs. A recent study has shown that hypermutated tumors are associated with elevated expression of immune genes related to tumor cytotoxicity, a significantly increased number of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs) and a higher expression of PD-1 and PD-L1. Accordingly, immune checkpoint inhibitors (like PD-1 and PD-L1) have shown remarkable efficacy against various hypermutated cancers such as lung carcinomas and melanomas. Taken together, the main objective of this project is the study of prognostic and predictive immune gene signatures and correlation with homologous recombination deficiency in HGSOC in order to 1) properly stratify HGSOC patients who will respond to NACT therapy, and 2) predict the potential efficacy of immunotherapy in NACT non-responder patients. We are using a patient population consisting of 90 matched samples HGSOC (n=45 pts), treated with carboplatin and paclitaxel standard dose NACT. The matched samples are baseline biopsy and samples from interval debulking surgery (IDS). For the first objective, we analyze and compare immune profile, immune gene signatures and correlation with HR deficiency in biopsy samples from responder and non-responder patients using Immunohistochemistry analysis, Nanostring Immuno-Oncology Assay and Next Generation Sequencing Gene Panels. Neither clear differences in immune profile nor significant differential gene expression patterns were observed between biopsy samples from responder and non-responder patients. For the second objective, we analyze and compare the immune profile and immune gene signatures of biopsy and surgery samples. Using the Nanostring Immuno-Oncology Assay, we found an increase of the inflammatory signature in surgical samples compared to their paired biopsy samples as well as an elevation in the number of TILs. Additionally, a significant decrease in the ratio Th1 cells vs TILs, Treg vs TILs and NK cells vs TILs was observed. In particular, the T cell population was found to be increased after NACT treatment, probably due to a major elevation of CD8 T cells. Finally, PD-1 shows a clear significantly increased expression after NACT. These results indicate that NACT in HGSOC patients promotes changes in the immune component that may favor combination of standard procedures with immunotherapy schedules in those patients with appropriated tissue microenvironment conditions.