Clinical trials targeting the immune tumor microenvironment (TME) in epithelial ovarian cancer (EOC) typically have included patients with heavily pre-treated advanced disease and demonstrated only marginal efficacy. A better understanding of how the EOC TME evolves with progression from primary to recurrent disease may inform future immunotherapy trials. Here, we evaluate the immune TME in primary and recurrent EOC using tissue microarrays. Our cohort included matched primary and recurrent tumors from 17 patients, and additional non-matched primary tumors from 20 patients and recurrent tumors from 15 patients. We stained for CD8, FOXP3 (regulatory T cells (Tregs)), CD68 (tumor associated macrophages (TAMs)), programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) by immunohistochemistry to interrogate the immune composition of the TME. Tregs increased in recurrent tumors compared to primary tumors (8.0 vs 14.2/HPF, p=0.0210). Higher TAM density was associated with higher levels of Treg and CD8+ T cell infiltrates in recurrent tumors (p=0.001 and p<0.001, respectively), and with higher Treg but not CD8+ T cell infiltrates in primary tumors (p=0.027 and p=0.200). TAM-dense recurrent tumors had increased PD-L1 on tumor cells and immune cells, whereas TAM-dense primary tumors had increased PD-L1 only on immune cells. Increased Tregs in primary tumors correlated with decreased time to first recurrence (17.0 vs 28.5 months, p=0.022). Conversely, increased Tregs in recurrent tumors correlated with longer overall survival (OS) from recurrence (median not met vs 20.0m, p=0.022). Although TAM density did not affect patient survival, analysis of matched primary and recurrent tumors revealed that patients with increased TAMs at recurrence (n=5) had a longer median OS from recurrence than patients without increased TAMs at recurrence (n=12). Tregs increased at recurrence in the majority of matched tumor pairs (n=12), but there was no correlation with survival. In conclusion, the TME of EOC is immunologically active. TAM-dense recurrent disease had higher CD8+ T cell and Treg infiltrates and PD-L1 expression. In this study, patients with increased cellular recruitment to the TME at recurrence had improved survival. Larger, more detailed studies characterizing the evolution of the TME with progression from primary EOC to recurrence are warranted.
Citation Format: Laureen S. Ojalvo, Elizabeth D. Thompson, Tian-Li Wang, Alan K. Meeker, Ie-Ming Shih, Amanda N. Fader, Ashley Cimino-Mathews, Leisha A. Emens. Profiling the immune tumor microenvironment in primary and recurrent epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3991. doi:10.1158/1538-7445.AM2017-3991