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

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

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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.

Original language	English
Article number	e1583547
Journal	OncoImmunology
Volume	8
Issue number	6
DOIs	https://doi.org/10.1080/2162402X.2019.1583547
Publication status	Published - 3 Jun 2019

Keywords

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

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10.1080/2162402X.2019.1583547

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Morcrette, G., Hirsch, T. Z., Badour, E., Pilet, J., Caruso, S., Calderaro, J., Martin, Y., Imbeaud, S., Letouzé, E., Rebouissou, S., Branchereau, S., Taque, S., Chardot, C., Guettier, C., Scoazec, J. Y., Fabre, M., Brugières, L., & Zucman-Rossi, J. (2019). APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. OncoImmunology, 8(6), Article e1583547. https://doi.org/10.1080/2162402X.2019.1583547

@article{b261c6078af94d1298ab197d49622380,

title = "APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures",

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 Bic{\^e}tre 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",

author = "Guillaume Morcrette and Hirsch, {Theo Z.} and Elise Badour and Jill Pilet and Stefano Caruso and Julien Calderaro and Yoann Martin and Sandrine Imbeaud and Eric Letouz{\'e} and Sandra Rebouissou and Sophie Branchereau and Sophie Taque and Christophe Chardot and Catherine Guettier and Scoazec, {Jean Yves} and Monique Fabre and Laurence Brugi{\`e}res and Jessica Zucman-Rossi",

note = "Publisher Copyright: {\textcopyright} 2019, {\textcopyright} 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.",

year = "2019",

month = jun,

day = "3",

doi = "10.1080/2162402X.2019.1583547",

language = "English",

volume = "8",

journal = "OncoImmunology",

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Morcrette, G, Hirsch, TZ, Badour, E, Pilet, J, Caruso, S, Calderaro, J, Martin, Y, Imbeaud, S, Letouzé, E, Rebouissou, S, Branchereau, S, Taque, S, Chardot, C, Guettier, C, Scoazec, JY, Fabre, M, Brugières, L & Zucman-Rossi, J 2019, 'APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures', OncoImmunology, vol. 8, no. 6, e1583547. https://doi.org/10.1080/2162402X.2019.1583547

TY - JOUR

T1 - APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

AU - Morcrette, Guillaume

AU - Hirsch, Theo Z.

AU - Badour, Elise

AU - Pilet, Jill

AU - Caruso, Stefano

AU - Calderaro, Julien

AU - Martin, Yoann

AU - Imbeaud, Sandrine

AU - Letouzé, Eric

AU - Rebouissou, Sandra

AU - Branchereau, Sophie

AU - Taque, Sophie

AU - Chardot, Christophe

AU - Guettier, Catherine

AU - Scoazec, Jean Yves

AU - Fabre, Monique

AU - Brugières, Laurence

AU - Zucman-Rossi, Jessica

PY - 2019/6/3

Y1 - 2019/6/3

N2 - 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.

AB - 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.

KW - Pediatric neoplasm

KW - adenomatous polyposis coli

KW - antitumor immunity

KW - immunogenic cell death

KW - liver tumor

UR - http://www.scopus.com/inward/record.url?scp=85063598295&partnerID=8YFLogxK

U2 - 10.1080/2162402X.2019.1583547

DO - 10.1080/2162402X.2019.1583547

M3 - Article

C2 - 31069152

AN - SCOPUS:85063598295

SN - 2162-4011

VL - 8

JO - OncoImmunology

JF - OncoImmunology

IS - 6

M1 - e1583547

ER -

APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures

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Keywords

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