Abstract 1590: High ICOS/FOXP3 Tregs content in the tumor microenvironment is associated with poorer survival in patients with hepatocellular carcinoma
Authors: Lu Li-Chun , Deantonio Cecilia , Mitchell Laura , Lee Yi-Hsuan , Shao Yu-Yun , Chen Ron , Cowan Marianne , Corser Matthew , Sherry Lorcan , Cheng Ann-Lii , Lin Chia-Chi , Quaratino Sonia , Sainson Richard C. , Hsu Chih-Hung 
Published: September 2020

Abstract
Background: Immunotherapy targeting co-stimulatory receptors of T cells is under active clinical investigation. Inducible co-stimulator (ICOS) is an important co-stimulatory receptor on effector T cells (Teffs) that also promotes tumor growth due to its high expression on regulatory T cells (Tregs). Human IgG1 anti-ICOS therapeutic antibodies may therefore induce antitumor immunity by stimulating ICOSLow Teffs and depleting ICOSHigh Tregs. This study explored the clinical significance of ICOS expression and Treg content in hepatocellular carcinoma (HCC).
Patients and Methods: We collected tumor tissues from HCC patients who received curative hepatectomy at the National Taiwan University Hospital, Taipei, Taiwan. Dual immunohistochemistry (IHC) was performed to evaluate the expression of ICOS and Foxp3. The cell density and distances between single- and dual-expressing cells in the tumor center, margin, and the peritumor area were quantitated by digital pathology. Associations between clinical outcome or clinical metadata and ICOS/Foxp3 expression were analyzed.
Results: A total of 142 patients (male: female= 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus (HBV) infection, 33 (23.2%) had chronic hepatitis C (HCV) infection, and 22 (15.5%) had no HBV/HCV infection. In this cohort, low AFP level (&lt; 20 ng/ml) and early stage, but not age, gender, or viral etiology, were significantly associated with improved overall survival (OS). However, the density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p&lt;0.001) in the tumor center than in the peritumor area especially in viral-related HCC. Similarly, patients with a high ratio of ICOS+Foxp3+/total Foxp3+ cells (p=0.074) or with high ICOS expression (p&lt;0.05) in the tumor center were associated with a shorter OS. Finally, a shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3- cells in the tumor center was significantly associated with a shorter OS (p&lt;0.05) suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teff cells.
Conclusions: A high proportion of Tregs in HCC tumors expresses ICOS, implying a strong immunosuppressive environment. Importantly, high ICOS expression in HCC tumors, a high ratio of ICOS+Foxp3+/total Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells are all associated with a poor OS, suggesting that targeting ICOS in this indication may provide clinical benefit (This work is partly supported by MOST 108-2314-B-002-073).
Citation Format: Li-Chun Lu, Cecilia Deantonio, Laura Mitchell, Yi-Hsuan Lee, Yu-Yun Shao, Ron Chen, Marianne Cowan, Matthew Corser, Lorcan Sherry, Ann-Lii Cheng, Chia-Chi Lin, Sonia Quaratino, Richard C. Sainson, Chih-Hung Hsu. High ICOS/FOXP3 Tregs content in the tumor microenvironment is associated with poorer survival in patients with hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1590.