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Original article
Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer
  1. Delphine Goehrig1,2,3,
  2. Jérémy Nigri4,
  3. Rémi Samain5,
  4. Zhichong Wu1,2,3,
  5. Paola Cappello6,
  6. Gaëlle Gabiane1,2,3,
  7. Xinyi Zhang1,2,3,
  8. Yajie Zhao1,2,3,
  9. In-San Kim7,
  10. Marie Chanal1,2,3,
  11. Roberta Curto6,
  12. Valerie Hervieu8,
  13. Christelle de La Fouchardière3,
  14. Francesco Novelli6,
  15. Pascale Milani9,10,
  16. Richard Tomasini4,
  17. Corinne Bousquet5,
  18. Philippe Bertolino1,2,3,
  19. Ana Hennino1,2,3
  1. 1 Cancer Research Center of Lyon, UMR INSERM 1052, Lyon, France
  2. 2 Université Lyon 1, Villeurbanne, France
  3. 3 Centre Léon Bérard, Lyon, France
  4. 4 INSERM 1068, CRCM, Marseille, France
  5. 5 UMR INSERM 1037, CRCT, Toulouse, France
  6. 6 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
  7. 7 KU-KIST School, Korea University, Seongbuk-gu, Korea
  8. 8 Hospices Civils de Lyon, HEH, Lyon, France
  9. 9 Ecole Normale Supérieure de Lyon, Lyon, France
  10. 10 Biomeca, Lyon
  1. Correspondence to Dr Ana Hennino, Cancer Research Center of Lyon, UMR INSERM 1052 Lyon France; ana.hennino{at}inserm.fr

Abstract

Objective Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.

Design We performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.

Results We identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.

Conclusions Our data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

  • immune response
  • pancreatic cancer
  • t lymphocytes

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • JN and RS contributed equally.

  • Contributors DG performed the experiments and analysed the data. JN, RS, PC, GG, XZ, ZW, YZ, RC and MC performed the experiments. PM performed the atomic force microscopy (AFM) experiments. VH and CDLF provided and analyed the human samples. I-SK provided the depleting βig-h3 antibody and designed the depletion experiments. PM performed the atomic force microscopy measurements. PB, RT, CB and FN discussed, interpreted the results and reviewed the writing of the manuscript. AH designed the experiments, analysed the data and wrote the manuscript. AH is the guarantor of this work and, as such, had full access to all data provided in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding This study was supported by grants from La Ligue Contre le Cancer (PB and AH),Fondation ARC and Cancerôpole Rhône Alpes Auvergne-Oncostarter (AH), INSERM Transfert (AH), Fondation pour la recheche médicale -FDT40493 (RS).Associazione Italiana Ricerca sul Cancro (FN); University of Turin-Compagnia di San Paolo, METAIMMUNOTHER (FN) and PANTHER (PC), Italian Ministry of Health, RF-2013-02354892 (FN).

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval CECCAPP Lyon.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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