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Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma

  • Julien Calderaro
    Correspondence
    Corresponding author. Address: Département de Pathologie, Centre Hospitalier Universitaire Henri Mondor, 51 av du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
    Affiliations
    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
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  • Florent Petitprez
    Affiliations
    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
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  • Etienne Becht
    Affiliations
    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
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  • Alexis Laurent
    Affiliations
    Service de Chirurgie Digestive et Hépatobiliaire, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France
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  • Théo Z. Hirsch
    Affiliations
    INSERM, UMR 1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hematologie, Paris, France
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  • Benoit Rousseau
    Affiliations
    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
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  • Alain Luciani
    Affiliations
    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
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  • Giuliana Amaddeo
    Affiliations
    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
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  • Jonathan Derman
    Affiliations
    Département de Pathologie, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France
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  • Cécile Charpy
    Affiliations
    Département de Pathologie, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Henri Mondor, Créteil, France
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  • Jessica Zucman-Rossi
    Affiliations
    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
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  • Author Footnotes
    † Co-senior authors.
    Wolf Herman Fridman
    Footnotes
    † Co-senior authors.
    Affiliations
    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
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  • Author Footnotes
    † Co-senior authors.
    Catherine Sautès-Fridman
    Footnotes
    † Co-senior authors.
    Affiliations
    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
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  • Author Footnotes
    † Co-senior authors.
Published:September 10, 2018DOI:https://doi.org/10.1016/j.jhep.2018.09.003

      Highlights

      • Intra-tumoral tertiary lymphoid structures are associated with decreased risk of early HCC relapse after surgery.
      • Presence of intra-tumoral tertiary lymphoid structures is not linked to the etiology of the underlying liver disease.
      • Our study suggests that tertiary lymphoid structures reflect ongoing, 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.

      Graphical abstract

      Keywords

      Linked Article

      • Prognosis assessment by pathologist: Is the detection of intratumoural tertiary lymphoid structures a reliable tool?
        Journal of HepatologyVol. 70Issue 1
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          Carcinogenesis is a complex multi-step process which reflects genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives.1 During this process, the immune system plays an important role in counterattacking the formation and progression of incipient neoplasia, late-stage tumours, and micro-metastases. This phenomenon, known as immunosurveillance, is triggered by the generation of tumour-associated antigens (TAAs) by the cancer cells through their malignant transformation.
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