Julien Calderaro1, Florent Petitprez2, Etienne Becht2, Alexis Laurent3, Théo Z Hirsch4, Benoit Rousseau5, Alain Luciani6, Giuliana Amaddeo7, Jonathan Derman8, Cécile Charpy8, Jessica Zucman-Rossi9, Wolf Herman Fridman10, Catherine Sautès-Fridman10. 1. Département de Pathologie, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France; Inserm U955, Team 18, Créteil, France; Université Paris-Est Créteil, France; INSERM UMR_S1138, Centre de Recherche des Cordeliers, Equipe cancer et immunité anti-tumorale, 15 rue de l'Ecole de Médecine, F75006 Paris, France. Electronic address: julien.calderaro@aphp.fr. 2. INSERM UMR_S1138, Centre de Recherche des Cordeliers, Equipe cancer et immunité anti-tumorale, 15 rue de l'Ecole de Médecine, F75006 Paris, France; Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France. 3. Service de Chirurgie Digestive et Hépatobiliaire, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France. 4. INSERM, UMR 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France. 5. Inserm U955, Team 18, Créteil, France; Université Paris-Est Créteil, France; Service d'Oncologie Médicale, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France. 6. Inserm U955, Team 18, Créteil, France; Université Paris-Est Créteil, France; Service d'Imagerie Médicale, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France. 7. Inserm U955, Team 18, Créteil, France; Université Paris-Est Créteil, France; Service d'Hépatologie, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France. 8. Département de Pathologie, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France. 9. INSERM, UMR 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 10. INSERM UMR_S1138, Centre de Recherche des Cordeliers, Equipe cancer et immunité anti-tumorale, 15 rue de l'Ecole de Médecine, F75006 Paris, France; Université Paris Descartes Paris 5, Sorbonne Paris Cite, UPMC Université Paris 6, F-75006 Paris, France.
Abstract
BACKGROUND & AIMS: Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver. METHODS: We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort). RESULTS: TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2 years after surgery, hazard ratio 0.46, p = 0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, p = 0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed. CONCLUSIONS: We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity. LAY SUMMARY: Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.
BACKGROUND & AIMS: Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver. METHODS: We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort). RESULTS: TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2 years after surgery, hazard ratio 0.46, p = 0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, p = 0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed. CONCLUSIONS: We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity. LAY SUMMARY: Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.
Authors: Josep M Llovet; Robin Kate Kelley; Augusto Villanueva; Amit G Singal; Eli Pikarsky; Sasan Roayaie; Riccardo Lencioni; Kazuhiko Koike; Jessica Zucman-Rossi; Richard S Finn Journal: Nat Rev Dis Primers Date: 2021-01-21 Impact factor: 52.329
Authors: K Li; Q Guo; X Zhang; X Dong; W Liu; A Zhang; Y Li; J Yan; G Jia; Z Zheng; W Tang; L Pan; M An; B Zhang; S Liu; B Fu Journal: Clin Exp Immunol Date: 2019-11-08 Impact factor: 4.330
Authors: Laia Bassaganyas; Roser Pinyol; Roger Esteban-Fabró; Laura Torrens; Sara Torrecilla; Catherine E Willoughby; Sebastià Franch-Expósito; Maria Vila-Casadesús; Itziar Salaverria; Robert Montal; Vincenzo Mazzaferro; Jordi Camps; Daniela Sia; Josep M Llovet Journal: Clin Cancer Res Date: 2020-09-01 Impact factor: 12.531