PD1 and TIM3 Expression is Associated with Very Early Hepatocellular Carcinoma Recurrence After Percutaneous Thermal Ablation

Abstract

Julien Ghelfi,1– 3,* Zuzana Macek Jilkova,1,3,4,* Christian Sengel,2 Bleuenn Brusset,4 Yann Teyssier,2 Charlotte Costentin,1,3,4 Marion Mercey-Ressejac,3,4 Lucile Dumolard,1,3 Marc Manceau,5 Eliott Mathieu,2 Ivan Bricault,1,2 Thomas Decaens1,3,4 1University of Grenoble-Alpes, Saint Martin d’Hères, France; 2Department of Radiology, Grenoble-Alpes University Hospital, Grenoble, France; 3Institute for Advanced Biosciences - INSERM U1209/CNRS UMR 5309/University of Grenoble-Alpes, La Tronche, France; 4Department of Hepatology and Gastrointestinal Medical Oncology, Grenoble-Alpes University Hospital, Grenoble, France; 5Clinical Pharmacology Unit, Inserm Clinical Research Center, Grenoble-Alpes University Hospital, Grenoble, France*These authors contributed equally to this workCorrespondence: Julien Ghelfi, Department of Radiology, Grenoble-Alpes University Hospital, Boulevard de la Chantourne, Grenoble, 38000, France, Tel [phone], Email [email protected] Zuzana Macek Jilkova, Department of Hepato-Gastroenterology, Grenoble-Alpes University Hospital, Boulevard de la Chantourne, Grenoble, 38000, France, Tel [phone], Email [email protected]: Percutaneous thermal ablation (PTA) is a cornerstone in the management of early-stage hepatocellular carcinoma (HCC). However, intrahepatic distant recurrence (IDR) occurs in the majority of patients after PTA. The aim of this study was to evaluate the immune signature associated with very early IDR.Patients and Methods: Thirty-one patients (26 men, 5 women; mean age:72.4 ± 8.6; age range:57– 86 years) who underwent PTA for HCC were included in this study. After PTA for HCC, patients were followed and later divided into two groups: a “very early recurrence” group in case of IDR within 12 months after PTA, and a “prolonged recurrence-free” group in case of no recurrence before 12 months of follow-up. Freshly harvested intratumoral and nontumoral liver tissues and peripheral blood were obtained before PTA and explored by multiparametric flow cytometry.Results: The frequency of PD1+CD4+ T cells was higher in the early recurrence group than in the prolonged recurrence-free group in the peripheral blood (24.3%, IQR: 22.3– 36.5 vs 14.0%, IQR: 11.5– 16.4, p< 0.0001), in the nontumoral liver (37.9%, IQR: 36.0– 50.0 vs 22.5%, IQR: 18.0– 29.9, p=0.0004), and in the tumor (37.6%, IQR: 32.3– 39.3 vs 24.0%, IQR: 20.0– 30.3, p=0.0137). Similarly, the frequency of TIM+CD8+ T cells was higher in the very early recurrence group in the peripheral blood (p=0.0021), non-tumoral liver (p=0.0012), and tumor (p=0.0239).Conclusion: The expression of immune checkpoint molecules, such as PD1 and TIM3 on T cells identified HCC patients at risk of very early IDR after PTA who would likely benefit from adjuvant immunotherapy. Thus, our study contributes to a better understanding of the potential association of PTA with adjuvant immunotherapies.Keywords: immune checkpoint molecules, predictive factors, hepatocellular carcinoma, percutaneous thermal ablation, intrahepatic distant recurrence

Keywords

• immune checkpoint molecules
• predictive factors
• hepatocellular carcinoma
• percutaneous thermal ablation
• intrahepatic distant recurrence.