APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

Guillaume Morcrette; Theo Z Hirsch; Elise Badour; Jill Pilet; Stefano Caruso; Julien Calderaro; Yoann Martin; Sandrine Imbeaud; Eric Letouzé; Sandra Rebouissou; Sophie Branchereau; Sophie Taque; Christophe Chardot; Catherine Guettier; Jean-Yves Scoazec; Monique Fabre; Laurence Brugières; Jessica Zucman-Rossi

doi:10.1080/2162402X.2019.1583547

APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019.

Authors

Guillaume Morcrette^{1

2

3}, Theo Z Hirsch^{1

2}, Elise Badour⁴, Jill Pilet^{1

2}, Stefano Caruso^{1

2}, Julien Calderaro^{1

2

5

6}, Yoann Martin^{1

2}, Sandrine Imbeaud^{1

2}, Eric Letouzé^{1

2}, Sandra Rebouissou^{1

2}, Sophie Branchereau⁷, Sophie Taque⁸, Christophe Chardot⁹, Catherine Guettier¹⁰, Jean-Yves Scoazec¹¹, Monique Fabre¹², Laurence Brugières¹³, Jessica Zucman-Rossi^{1

2

14}

Affiliations

¹ Centre de Recherche des Cordeliers, Functional Genomics of Solid Tumors laboratory, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France.
² Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.
³ Service de Pathologie Pédiatrique, Assistance Publique Hôpitaux de Paris, Hôpital Robert Debré, Paris, France.
⁴ Service de pédiatrie, Centre Hospitalier de la Côte Basque, Bayonne, France.
⁵ Service d'anatomopathologie, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Créteil, France.
⁶ Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, France.
⁷ Service de chirurgie pédiatrique, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Université Paris-Saclay, Le Kremlin, France.
⁸ Département de Médecine de l'Enfant et l'Adolescent, CHU de Rennes, France.
⁹ Service de Chirurgie viscérale pédiatrique, Assistance Publique Hôpitaux de Paris, Hôpital Necker-Enfants malades, Paris, France.
¹⁰ Service d'anatomie et de cytologie pathologiques, Hôpitaux Universitaires Paris Sud, Assistance Publique Hôpitaux de Paris Le Kremlin Bicêtre, Faculté de Médecine Paris Sud, INSERM, Paris, France.
¹¹ Service d'anatomie et de cytologie pathologiques, Gustave Roussy Cancer Center, Villejuif, France.
¹² Service d'anatomie et de cytologie pathologiques, Assistance Publique Hôpitaux de Paris, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
¹³ Département de cancérologie de l'Enfant et l'adolescent, Gustave Roussy Cancer Center, Villejuif, France.
¹⁴ Département de cancérologie, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.

Abstract

Hepatoblastoma (HB) is the most common liver cancer in children. We aimed to characterize HB related to APC (Adenomatous Polyposis Coli) germline mutation (APC-HB). This French multicentric retrospective study included 12 APC-HB patients under 5 at diagnosis. Clinical features of APC-HB were compared to the French SIOPEL2-3 cohort of HB patients. Molecular and histopathological analyses of APC-HB were compared to 15 consecutive sporadic HB treated at Bicêtre hospital from 2013 to 2015 (non-APC-HB). APC-HB patients have a peculiar spectrum of germline APC mutations, with no events in the main hotspot of classical APC mutations at codon 1309 (P < .05). Compared to sporadic HB, they have similar clinical features including good prognosis since all patients are alive in complete remission at last follow-up. APC-HB are mostly well-limited tumors with fetal predominance and few mesenchymal components. All APC-HB have an activated Wnt/β-catenin pathway without CTNNB1 mutation, confirming that germline APC and somatic CTNNB1 mutations are mutually exclusive (P < .001). Pathological reviewing identified massive intratumor tertiary lymphoid structures (TLS) containing both lymphocytes and antigen-presenting cells in all 11 APC-HB cases who received cisplatin-based neoadjuvant chemotherapy but not in five pre-chemotherapy samples (four paired biopsies and one patient resected without chemotherapy), indicating that these TLS are induced by chemotherapy (P < .001). Conclusion: APC-HB show a good prognosis, they are all infiltrated by cisplatin-induced TLS, a feature only retrieved in a minority of non-APC-HB. This suggests that APC inactivation can synergize with cisplatin to induce an immunogenic cell death that initiates an anti-tumor immune response.

Keywords: Pediatric neoplasm; adenomatous polyposis coli; antitumor immunity; immunogenic cell death; liver tumor.

Publication types

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

Grants and funding

FUNGEST team is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmunology (investissement d’avenir), Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, Fondation Mérieux, SFCE (Société Française de Lutte Contre les Cancers et les Leucémies de l’Enfant), Fédération Enfants Santé, Etoile de Martin, l’Association Hubert Gouin « Enfance et Cancer ». GM was supported by CARPEM. TZH was supported by Région Ile de France and then Fondation d’Entreprise Bristol-Myers Squibb pour la Recherche en Immuno-Oncologie. JP is supported by the Fondation Pour La Recherche Médicale, FRM grant number: ECO20170637540.