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Smart exosomes with lymph node homing and immune-amplifying capacities for enhanced immunotherapy of metastatic breast cancer.

ABSTRACT: Tumor-draining lymph nodes (TDLNs) are the primary sites to initiate immune responses against cancer, as well as the origin of metastasis for most breast cancer cases. Reverting the immunosuppression microenvironment in TDLNs is critical to improving the outcome of the malignancy, though still a big technical challenge. In this study, a type of smart exosomes was developed in which the exosome surface was functionally engineered with CD62L (L-selectin, a gene for lymphocyte homing to lymph nodes) and OX40L (CD134L, a gene for effector T cell expansion and regulatory T cell [Treg] inhibition) by forced expression of the genes in the donor cells. Compared with control exosomes, the smart exosomes displayed strong TDLN homing capacity in the 4T1 syngeneic mouse model. Moreover, injection of the smart exosomes activated effector T cells and inhibited Treg induction, thereby amplifying the antitumor immune response and inhibiting tumor development. Together, the engineered smart exosomes provide a novel nanoplatform for TDLN-targeted delivery and cancer immunotherapy.

SUBMITTER: Ji P

PROVIDER: S-EPMC8560825 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Smart exosomes with lymph node homing and immune-amplifying capacities for enhanced immunotherapy of metastatic breast cancer.

Ji Panpan P Yang Zheng Z Li Hua H Wei Mengying M Yang Guodong G Xing Helin H Li Qiuyun Q

Molecular therapy. Nucleic acids 20211019

Tumor-draining lymph nodes (TDLNs) are the primary sites to initiate immune responses against cancer, as well as the origin of metastasis for most breast cancer cases. Reverting the immunosuppression microenvironment in TDLNs is critical to improving the outcome of the malignancy, though still a big technical challenge. In this study, a type of smart exosomes was developed in which the exosome surface was functionally engineered with CD62L (L-selectin, a gene for lymphocyte homing to lymph nodes ...[more]

PMID: 34760340

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Project description:ObjectivesTo assess 3-Tesla (3-T) ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI in detecting lymph node (LN) metastases for resectable adenocarcinomas of the pancreas, duodenum, or periampullary region in a node-to-node validation against histopathology.MethodsTwenty-seven consecutive patients with a resectable pancreatic, duodenal, or periampullary adenocarcinoma were enrolled in this prospective single expert centre study. Ferumoxtran-10-enhanced 3-T MRI was performed pre-surgery. LNs found on MRI were scored for suspicion of metastasis by two expert radiologists using a dedicated scoring system. Node-to-node matching from in vivo MRI to histopathology was performed using a post-operative ex vivo 7-T MRI of the resection specimen. Sensitivity and specificity were calculated using crosstabs.ResultsEighteen out of 27 patients (median age 65 years, 11 men) were included in the final analysis (pre-surgery withdrawal n = 4, not resected because of unexpected metastases peroperatively n = 2, and excluded because of inadequate contrast-agent uptake n = 3). On MRI 453 LNs with a median size of 4.0 mm were detected, of which 58 (13%) were classified as suspicious. At histopathology 385 LNs with a median size of 5.0 mm were found, of which 45 (12%) were metastatic. For 55 LNs node-to-node matching was possible. Analysis of these 55 matched LNs, resulted in a sensitivity and specificity of 83% (95% CI: 36-100%) and 92% (95% CI: 80-98%), respectively.ConclusionUSPIO-enhanced MRI is a promising technique to preoperatively detect and localise LN metastases in patients with pancreatic, duodenal, or periampullary adenocarcinoma.Clinical relevance statementDetection of (distant) LN metastases with USPIO-enhanced MRI could be used to determine a personalised treatment strategy that could involve neoadjuvant or palliative chemotherapy, guided resection of distant LNs, or targeted radiotherapy.RegistrationThe study was registered on clinicaltrials.gov NCT04311047. https://clinicaltrials.gov/ct2/show/NCT04311047?term=lymph+node&cond=Pancreatic+Cancer&cntry=NL&draw=2&rank=1 .Key pointsLN metastases of pancreatic, duodenal, or periampullary adenocarcinoma cannot be reliably detected with current imaging. This technique detected LN metastases with a sensitivity and specificity of 83% and 92%, respectively. MRI with ferumoxtran-10 is a promising technique to improve preoperative staging in these cancers.

Dataset Information

Smart exosomes with lymph node homing and immune-amplifying capacities for enhanced immunotherapy of metastatic breast cancer.

Publications

Smart exosomes with lymph node homing and immune-amplifying capacities for enhanced immunotherapy of metastatic breast cancer.

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