Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

Özdemir, Berna C.; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L.; Zheng, Xiaofeng; Wu, Chia-Chin; Simpson, Tyler R.; Laklai, Hanane; Sugimoto, Hikaru; Kahlert, Christoph; Novitskiy, Sergey V.; Jesus-Acosta, Ana De; Sharma, Padmanee; Heidari, Pedram; Mahmood, Umar; Chin, Lynda; Moses, Harold L.; Weaver, Valerie M.; Maitra, Anirban; Allison, James P.; LeBleu, Valerie S.; Kalluri, Raghu

doi:10.1016/j.ccr.2014.04.005

Cited by 2,020 publications

(2,042 citation statements)

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“…Nevertheless, at this stage more basic knowledge regarding targeting of PSCs and desmoplasia is needed. Recent publication in PDAC research question whether inhibition of stroma and fibrosis is advantageous as, on one hand, it may improve the drug delivery but, on the other hand, it may remove restrain on tumour growth and metastasis 45, 46, 47…”

Section: Discussionmentioning

confidence: 99%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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The ATP‐gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu‐1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu‐1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7‐/‐ animals. PancTu‐1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120‐treated mice showed reduced bioluminescence compared to saline‐treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120‐treated tumours.

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Section: Discussionmentioning

confidence: 99%

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Giannuzzo

Saccomano

Napp

et al. 2016

Intl Journal of Cancer

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“…Our work points toward a detrimental role of PSCs by promoting immunosuppression while another new study suggests that the presence of PSCs-related fibrosis could prevents the recruitment of Tregs into PDAC. 10 Now, further basic and clinical investigations are needed to clarify the PSCs-immune system interplay in pancreatic cancer in order to find the right multi-targeting strategy for improving current treatment.…”

Section: Ip-10/cxcl10 Attracts Regulatory T Cellsmentioning

confidence: 99%

IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer

et al. 2015

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“…32 Similar reports came from another study in which authors demonstrated that depleting myofibroblasts correlated with reduced survival, tumor undifferentiating, invasion and increased epithelial-to-mesenchymal transition. 33 Therefore, both studies underscore the need for caution in targeting carcinoma-associated fibroblasts. Depletion of myeloid cells, by pharmacological approaches, was instead efficient in increasing intratumoral accumulation of activated CD8…”

Section: Gr1mentioning

confidence: 99%

Anti-α-enolase antibody limits the invasion of myeloid-derived suppressor cells and attenuates their restraining effector T cell response

et al. 2015

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Pancreatic Ductal Adenocarcinoma (PDA) is a very aggressive tumor for which effective therapeutical strategies are still lacking. Globally, the 5 y survival rate is 5-7% and surgery is the only potentially curative treatment. Immunotherapy represents a novel possibility for treating PDA, and myeloid-derived suppressor cells (MDSC), which are increased in cancer patients and correlate with metastatic burden and cancer stage, offer a new target in cancer therapy. We have previously shown that antibodies against the PDA-associated antigen a-enolase (ENO1) are detected in more than 60% of PDA patients and correlate with a better prognosis. Furthermore, ENO1-DNA vaccination in mice induced anti-ENO1 antibodies that mediated antitumor activity. In this study, the effects of anti-ENO1 binding on MDSC functions and on the T cell response were evaluated. Here, we show that MDSC express ENO1 on their surface, which increased after LPS stimulation. Moreover, anti-ENO1 mAb inhibited adhesion to endothelial cells, as well as in vitro and in vivo migration. Similarly, after ENO1 mAb treatment of MDSC, arginase activity decreased, while the secretion of pro-inflammatory cytokines (particularly IL-6) increased, and co-stimulatory molecule expression and suppression functions were only partially affected. Finally, we found that activated T cells in the presence of anti-ENO1 mAb-treated MDSC increased IFNg and IL-17 secretion and decreased IL-10 and TGFb secretion compared to control MDSC. In conclusion, anti-ENO1 antibodies may inhibit in vivo the infiltration into the tumor microenvironment of MDSC, and attenuate their restraining of effector T cell response, opening a new perspective to render PDA immunotherapy more effective.

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Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival

Cited by 2,020 publications

References 51 publications

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

IP-10/CXCL10 attracts regulatory T cells: Implication for pancreatic cancer

Anti-α-enolase antibody limits the invasion of myeloid-derived suppressor cells and attenuates their restraining effector T cell response

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