APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

Guillaume Morcrette; Theo 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

Guillaume Morcrette ^{1, 2, 3} Theo Hirsch ^{1, 2} Elise Badour ⁴ 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 Branchereau ⁷ Sophie Taque ⁸ Christophe Chardot ⁹ Catherine Guettier ¹⁰ Jean-Yves Scoazec ¹¹ Monique Fabre ¹² Laurence Brugières ¹³ Jessica Zucman-Rossi ^{1, 2, 14}

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

2 Labex OncoImmunology, Equipe labellisée Ligue Contre le Cancer

3 Pathologie pédiatrique

4 Service de pédiatrie [CH de la Côte Basque, Bayonne]

5 Service d'Anatomopathologie [Hôpital Henri Mondor - APHP]

6 IMRB - Institut Mondor de Recherche Biomédicale

7 Service de chirurgie pédiatrique [Hôpital Bicêtre - APHP]

8 Département de Médecine de l’Enfant et l’Adolescent [CHU de Rennes]

9 Service de Chirurgie Viscérale Pédiatrique [Hôpital Necker-Enfants malades - APHP]

10 Service d’anatomie et de cytologie pathologiques [Hôpital le Kremlin Bicêtre - APHP]

11 Service d’anatomie et de cytologie pathologiques [Gustave Roussy, Villejuif]

12 Service d'anatomie pathologique [CHU Necker]

13 Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy]

14 Département de cancérologie [Hôpital Européen Georges Pompidou - APHP]

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

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Cancer

Life Sciences [q-bio] / Genetics / Human genetics

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APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

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