Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Delphine Goehrig, Jérémy Nigri, Rémi Samain, Zhichong Wu, Paola Cappello, Gaëlle Gabiane, Xinyi Zhang, Yajie Zhao, In-San Kim, Marie Chanal, Roberta Curto, Valerie Hervieu, Christelle De La Fouchardière, Francesco Novelli, Pascale Milani, Richard Tomasini, Corinne Bousquet, Philippe Bertolino, Ana Hennino

Research output: Contribution to journalArticle

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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;Kras G12D, pdx1-Cre;Kras G12D;Ink4a/Arf fl/fl, pdx1-Cre;Kras G12D; p53 R172H 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.

Original languageEnglish
Pages (from-to)693-707
Number of pages15
JournalGut
Volume68
Issue number4
DOIs
Publication statusPublished - 2019 Apr 1

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Tumor Microenvironment
Pancreatic Neoplasms
Tumor Escape
Neoplasms
Proteins
Growth
Macrophages
T-Lymphocytes
Atomic Force Microscopy
Extracellular Matrix Proteins
Tumor Burden
Transgenic Mice
Fluorescent Antibody Technique
Flow Cytometry
Adenocarcinoma
Immunohistochemistry
Injections
Antibodies

Keywords

  • immune response
  • pancreatic cancer
  • t lymphocytes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Goehrig, D., Nigri, J., Samain, R., Wu, Z., Cappello, P., Gabiane, G., ... Hennino, A. (2019). Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer. Gut, 68(4), 693-707. https://doi.org/10.1136/gutjnl-2018-317570

Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer. / Goehrig, Delphine; Nigri, Jérémy; Samain, Rémi; Wu, Zhichong; Cappello, Paola; Gabiane, Gaëlle; Zhang, Xinyi; Zhao, Yajie; Kim, In-San; Chanal, Marie; Curto, Roberta; Hervieu, Valerie; De La Fouchardière, Christelle; Novelli, Francesco; Milani, Pascale; Tomasini, Richard; Bousquet, Corinne; Bertolino, Philippe; Hennino, Ana.

In: Gut, Vol. 68, No. 4, 01.04.2019, p. 693-707.

Research output: Contribution to journalArticle

Goehrig, D, Nigri, J, Samain, R, Wu, Z, Cappello, P, Gabiane, G, Zhang, X, Zhao, Y, Kim, I-S, Chanal, M, Curto, R, Hervieu, V, De La Fouchardière, C, Novelli, F, Milani, P, Tomasini, R, Bousquet, C, Bertolino, P & Hennino, A 2019, 'Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer', Gut, vol. 68, no. 4, pp. 693-707. https://doi.org/10.1136/gutjnl-2018-317570
Goehrig D, Nigri J, Samain R, Wu Z, Cappello P, Gabiane G et al. Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer. Gut. 2019 Apr 1;68(4):693-707. https://doi.org/10.1136/gutjnl-2018-317570
Goehrig, Delphine ; Nigri, Jérémy ; Samain, Rémi ; Wu, Zhichong ; Cappello, Paola ; Gabiane, Gaëlle ; Zhang, Xinyi ; Zhao, Yajie ; Kim, In-San ; Chanal, Marie ; Curto, Roberta ; Hervieu, Valerie ; De La Fouchardière, Christelle ; Novelli, Francesco ; Milani, Pascale ; Tomasini, Richard ; Bousquet, Corinne ; Bertolino, Philippe ; Hennino, Ana. / Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer. In: Gut. 2019 ; Vol. 68, No. 4. pp. 693-707.
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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;Kras G12D, pdx1-Cre;Kras G12D;Ink4a/Arf fl/fl, pdx1-Cre;Kras G12D; p53 R172H 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.",
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AU - Nigri, Jérémy

AU - Samain, Rémi

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AU - Cappello, Paola

AU - Gabiane, Gaëlle

AU - Zhang, Xinyi

AU - Zhao, Yajie

AU - Kim, In-San

AU - Chanal, Marie

AU - Curto, Roberta

AU - Hervieu, Valerie

AU - De La Fouchardière, Christelle

AU - Novelli, Francesco

AU - Milani, Pascale

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N2 - 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;Kras G12D, pdx1-Cre;Kras G12D;Ink4a/Arf fl/fl, pdx1-Cre;Kras G12D; p53 R172H 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.

AB - 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;Kras G12D, pdx1-Cre;Kras G12D;Ink4a/Arf fl/fl, pdx1-Cre;Kras G12D; p53 R172H 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.

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