Dataset Information

Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice.

ABSTRACT: Aim:Immunotherapies blocking the CD47-SIRP? pathway by targeting CD47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRP? exhibits relatively restricted tissue expression, SIRP? antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies (mAbs) against CD47 and/or SIRP? on gastroenterological tumors in syngeneic immunocompetent mouse models. Methods:We used in vitro and in vivo phagocytosis assays in C57BL/6J (B6) mice to investigate anti-CD47/SIRP? mAb effects on Hepa1-6 and CMT93 originating from B6 mice. The influence of these mAbs on macrophage transmigration was also assessed. To investigate anti-SIRP? mAb therapy-induced inhibitory effects on sporadic colon cancer growth, we used a CDX2P9.5-NLS Cre;APC + /FLOX (CPC-APC) mouse model. Results:Systemic anti-SIRP? mAb administration significantly increased Hepa1-6 and CMT93 cell susceptibility to macrophage phagocytosis, both in vitro and in vivo. Conversely, similarly administered anti-CD47 mAb did not promote macrophage phagocytosis of target cells, whereas cells incubated with anti-CD47 mAb prior to inoculation were more susceptible to macrophage phagocytosis. In vitro cell migration assays revealed that binding with anti-CD47 mAb inhibited macrophage transmigration. Anti-SIRP? mAb treatment inhibited tumor progression in CPC-APC mice and significantly improved overall survival. Anti-CD47 mAb administration in vivo eliminated the phagocytosis-promoting CD47 blockade effect, probably by inhibiting macrophage transmigration/chemotaxis. In contrast, anti-SIRP? mAb exhibited enhanced macrophage phagocytic activity and marked anti-tumor effects against gastroenterological malignancies. Conclusion:SIRP? mAb augmentation of macrophage phagocytic activity may represent an effective treatment strategy for human gastrointestinal tumors.

SUBMITTER: Abe T

PROVIDER: S-EPMC6236110 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice.

Abe Tomoyuki T Tanaka Yuka Y Piao Jinlian J Tanimine Naoki N Oue Naohide N Hinoi Takao T Garcia Noel Verjan NV Miyasaka Masayuki M Matozaki Takashi T Yasui Wataru W Ohdan Hideki H

Annals of gastroenterological surgery 20180910 6

<h4>Aim</h4>Immunotherapies blocking the CD47-SIRPα pathway by targeting CD47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRPα exhibits relatively restricted tissue expression, SIRPα antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies (mAbs) against CD47 and/or SIRPα on gastroenterological tumors in syngeneic immunocompetent mouse models. ...[more]

PMID: 30460349

Similar Datasets

Project description:BackgroundCancer stem cells (CSCs) are considered responsible for the recurrence and chemoresistance of cancer. Dysregulated autophagy is highly prevalent in many types of cancer including pancreatic cancer and has been implicated in cytoprotection and tumor promotion. This study aimed to investigate the role of autophagy in regulating cancer stemness and chemoresistance of pancreatic cancer.MethodsThe correlation between autophagy and CSCs and its clinical significance were analyzed using pancreatic cancer tissue microarrays. Genetic and pharmacological approaches were applied to explore the function of autophagy on CSC activity and gemcitabine resistance of pancreatic cancer cells in vitro and in vivo.ResultsLC3 expression positively correlated with the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), CD44, and CD133 in pancreatic cancer tissues. High coexpression of LC3/ALDH1 was associated with both poor overall survival and progression-free survival. In pancreatic cancer cell lines, higher LC3-II expression was observed in the sphere-forming cells than in the bulk cells. Blockade of autophagy by silencing ATG5, ATG7, and BECN1 or the administration of autophagy inhibitor chloroquine markedly reduced the CSC populations, ALDH1 activity, sphere formation, and resistance to gemcitabine in vitro and in vivo. Furthermore, osteopontin (OPN) was found to stimulate LC3-II, ALDH1, CD44, and CD133 expression in PANC-1 cells, whereas this effect could be prevented by OPN knockdown and autophagy blockade. After treatment with various inhibitors against the major signaling pathways downstream of OPN, only the inhibitor of NF-κB activation, BAY 1170-82, could effectively counteract OPN-induced autophagy and CSC activity. According to the histochemical results, pancreatic cancer patients manifesting high levels of OPN/LC3/ALDH1 and OPN/CD44/CD133 had poor survival.ConclusionsInduction of autophagy mediated by OPN/NF-κB signaling is required for maintenance of pancreatic CSC activity. Combination of gemcitabine with pharmacological autophagy inhibitors is a promising therapeutic strategy for pancreatic cancer.

Dataset Information

Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice.

Publications

Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets