Dynamic of systemic immunity and its impact on tumor recurrence after radiofrequency ablation of hepatocellular carcinoma

Philippe Rochigneux; Jean-Charles Nault; Françoise Mallet; Anne-Sophie Chretien; Nathalie Barget; Alejandro J Garcia; Lucie Del Pozo; Valérie Bourcier; Lorraine Blaise; Véronique Grando-Lemaire; Gisèle N'Kontchou; Pierre Nahon; Olivier Seror; Marianne Ziol; Nathalie Ganne-Carrié; Daniel Olive

doi:10.1080/2162402X.2019.1615818

Dynamic of systemic immunity and its impact on tumor recurrence after radiofrequency ablation of hepatocellular carcinoma

Oncoimmunology. 2019 May 25;8(8):1615818. doi: 10.1080/2162402X.2019.1615818. eCollection 2019.

Authors

Philippe Rochigneux^{1

2}, Jean-Charles Nault^{3

4}, Françoise Mallet⁵, Anne-Sophie Chretien^{2

5}, Nathalie Barget⁶, Alejandro J Garcia⁷, Lucie Del Pozo⁴, Valérie Bourcier⁴, Lorraine Blaise⁴, Véronique Grando-Lemaire⁴, Gisèle N'Kontchou⁴, Pierre Nahon^{3

4}, Olivier Seror^{3

8}, Marianne Ziol^{3

9}, Nathalie Ganne-Carrié^{3

4}, Daniel Olive^{2

5}

Affiliations

¹ Medical Oncology Department, Paoli-Calmettes Institute, Marseille, France.
² Team Immunity and Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
³ Inserm UMR 1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
⁴ Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, APHP, Bondy, Unité de Formation et de Recherche Santé Médecine et Biologie humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
⁵ Immunomonitoring Platform, Institut Paoli-Calmettes, Marseille, France.
⁶ Tumor Biobank, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, APHP, Bondy, France.
⁷ Core Cytometry Laboratory, University of California at Los Angeles, Los Angeles, USA.
⁸ Radiology Department, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, APHP, Bondy, France.
⁹ Pathology Department, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, APHP, Bondy, Unité de Formation et de Recherche Santé Médecine et Biologie humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.

Abstract

Background: Percutaneous radiofrequency ablation (RFA) is one of the main treatments of small hepatocellular carcinoma (HCC). However, it remains unclear whether this local treatment can induce systemic immune variations. Methods: We conducted a prospective study in a tertiary center including consecutive cirrhotic patients with unifocal HCC<5 cm treated by a first RFA between 2010 and 2014. Peripheral blood mononuclear cells were isolated on the day before (D0), day after (D1) and month after RFA (M1). Frequencies and phenotypes of myeloid cells, T cells, and NK cells were compared between timepoints. Overall recurrence and associated variables were estimated using Kaplan-Meier, log-rank and Cox proportional-hazards models. Results: 80 patients were included (69% male, median age: 67 years old). Main aetiologies of HCC were alcohol (51%), hepatitis C virus (45%), non-alcoholic steatohepatitis (36%) and hepatitis B virus (9%). Median overall survival was 55 months (M); median progression-free survival was 29.5M. Among innate immune populations, we observed variations between D0, D1 and M1 in NKp30+ NK cells (p < .0001) and in plasmacytoid dendritic cells (pDC, p < .01). Concerning adaptive immunity, we observed variations in CD8 Central Memory (p < .05) and CD28+ CD8 Central Memory (p < .01). An early dynamic (D0/D1) of activated NKp30⁺ NK cells was associated with a decreased overall recurrence (log-rank, p = .016, median delay 25.1 vs 40.6 months). In contrast, a late dynamic (D1/M1) of immature NK cells (CD56^bright) and altered myeloid DC (PDL1⁺) was associated with an increased overall recurrence (log-rank, p = .011 and p = .0044, respectively). In multivariate analysis, variation of immature NK cells predicts tumor recurrence independently of classical clinical prognostic features (HR = 2.41, 95% CI: 1.15-5.057), p = .019). Conclusions: Percutaneous RFA of small HCC leads to systemic modifications of innate and adaptive immunity closely linked with overall tumor recurrence.

Keywords: NK cells; PDL1; Radiofrequency ablation; dendritic cells; immune monitoring; innate immunity.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

Grant FAR from SNFGE (Société Nationale Française de Gastro-Entérologie). No funding source were involved in the interpretation of data and the writing of the manuscript.