RT Journal Article
SR Electronic
T1 Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 693
OP 707
DO 10.1136/gutjnl-2018-317570
VO 68
IS 4
A1 Delphine Goehrig
A1 Jérémy Nigri
A1 Rémi Samain
A1 Zhichong Wu
A1 Paola Cappello
A1 Gaëlle Gabiane
A1 Xinyi Zhang
A1 Yajie Zhao
A1 In-San Kim
A1 Marie Chanal
A1 Roberta Curto
A1 Valerie Hervieu
A1 Christelle de La Fouchardière
A1 Francesco Novelli
A1 Pascale Milani
A1 Richard Tomasini
A1 Corinne Bousquet
A1 Philippe Bertolino
A1 Ana Hennino
YR 2019
UL http://gut.bmj.com/content/68/4/693.abstract
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;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.