PMID- 35148751 OWN - NLM STAT- MEDLINE DCOM- 20220404 LR - 20220405 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 21 IP - 1 DP - 2022 Feb 11 TI - Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer. PG - 45 LID - 10.1186/s12943-022-01515-x [doi] LID - 45 AB - BACKGROUND: Dendritic cells (DCs) are central for the initiation and regulation of innate and adaptive immunity in the tumor microenvironment. As such, many kinds of DC-targeted vaccines have been developed to improve cancer immunotherapy in numerous clinical trials. Targeted delivery of antigens and adjuvants to DCs in vivo represents an important approach for the development of DC vaccines. However, nonspecific activation of systemic DCs and the preparation of optimal immunodominant tumor antigens still represent major challenges. METHODS: We loaded the immunogenic cell death (ICD) inducers human neutrophil elastase (ELANE) and Hiltonol (TLR3 agonist) into alpha-lactalbumin (alpha-LA)-engineered breast cancer-derived exosomes to form an in situ DC vaccine (HELA-Exos). HELA-Exos were identified by transmission electron microscopy, nanoscale flow cytometry, and Western blot analysis. The targeting, killing, and immune activation effects of HELA-Exos were evaluated in vitro. The tumor suppressor and immune-activating effects of HELA-Exos were explored in immunocompetent mice and patient-derived organoids. RESULTS: HELA-Exos possessed a profound ability to specifically induce ICD in breast cancer cells. Adequate exposure to tumor antigens and Hiltonol following HELA-Exo-induced ICD of cancer cells activated type one conventional DCs (cDC1s) in situ and cross-primed tumor-reactive CD8(+) T cell responses, leading to potent tumor inhibition in a poorly immunogenic triple negative breast cancer (TNBC) mouse xenograft model and patient-derived tumor organoids. CONCLUSIONS: HELA-Exos exhibit potent antitumor activity in both a mouse model and human breast cancer organoids by promoting the activation of cDC1s in situ and thus improving the subsequent tumor-reactive CD8(+) T cell responses. The strategy proposed here is promising for generating an in situ DC-primed vaccine and can be extended to various types of cancers. Scheme 1. Schematic illustration of HELA-Exos as an in situ DC-primed vaccine for breast cancer. (A) Allogenic breast cancer-derived exosomes isolated from MDA-MB-231 cells were genetically engineered to overexpress alpha-LA and simultaneously loaded with the ICD inducers ELANE and Hiltonol (TLR3 agonist) to generate HELA-Exos. (B) Mechanism by which HELA-Exos activate DCs in situ in a mouse xenograft model ofTNBC. HELA-Exos specifically homed to the TME and induced ICD in cancer cells, which resulted in the increased release of tumor antigens, Hiltonol, and DAMPs, as well as the uptake of dying tumor cells by cDC1s. The activated cDC1s then cross-primed tumor-reactive CD8+ T cell responses. (C) HELA-Exos activated DCs in situ in the breast cancer patient PBMC-autologous tumor organoid coculture system. ABBREVIATIONS: DCs: dendritic cells; alpha-LA: alpha-lactalbumin; HELA-Exos: Hiltonol-ELANE-alpha-LA-engineered exosomes; ICD: immunogenic cell death; ELANE: human neutrophil elastase; TLR3: Toll-like receptor 3; TNBC: triple-negative breast cancer; TME: tumor microenvironment; DAMPs: damage-associated molecular patterns; cDC1s: type 1 conventional dendritic cells; PBMCs: peripheral blood mononuclear cells. CI - (c) 2022. The Author(s). FAU - Huang, Lanxiang AU - Huang L AD - Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuhan, Wuchang District, China. AD - Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Rong, Yuan AU - Rong Y AD - Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuhan, Wuchang District, China. AD - Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Tang, Xuan AU - Tang X AD - Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuhan, Wuchang District, China. AD - Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Yi, Kezhen AU - Yi K AD - Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuhan, Wuchang District, China. AD - Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Qi, Peng AU - Qi P AD - Department of Thyroid and Breast Surgery, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, China. FAU - Hou, Jinxuan AU - Hou J AD - Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Liu, Weihuang AU - Liu W AD - Medical Research Center for Structural Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, China. FAU - He, Yuan AU - He Y AD - Medical Research Center for Structural Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, China. FAU - Gao, Xing AU - Gao X AD - Animal Experiment Center, Zhongnan Hospital of Wuhan University, Wuhan, China. FAU - Yuan, Chunhui AU - Yuan C AD - Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China. Chunhuii.yuen@whu.edu.cn. AD - Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Chunhuii.yuen@whu.edu.cn. FAU - Wang, Fubing AU - Wang F AD - Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, No.169 Donghu Road, Wuhan, Wuchang District, China. wfb20042002@sina.com. AD - Center for Single-Cell Omics and Tumor Liquid Biopsy, Zhongnan Hospital of Wuhan University, Wuhan, China. wfb20042002@sina.com. AD - Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China. wfb20042002@sina.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220211 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (Cancer Vaccines) RN - 0 (Vaccines) SB - IM MH - Animals MH - *Breast Neoplasms/genetics/metabolism/therapy MH - *Cancer Vaccines MH - Cell Line, Tumor MH - Dendritic Cells MH - *Exosomes MH - Female MH - Humans MH - Leukocytes, Mononuclear MH - Mice MH - Tumor Microenvironment MH - *Vaccines/metabolism PMC - PMC8831689 OTO - NOTNLM OT - Breast cancer OT - DC vaccine OT - Hiltonol OT - Immunogenic cell death OT - Tumor-derived exosomes OT - Type 1 conventional dendritic cells COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/02/13 06:00 MHDA- 2022/04/05 06:00 PMCR- 2022/02/11 CRDT- 2022/02/12 05:25 PHST- 2021/11/22 00:00 [received] PHST- 2022/01/19 00:00 [accepted] PHST- 2022/02/12 05:25 [entrez] PHST- 2022/02/13 06:00 [pubmed] PHST- 2022/04/05 06:00 [medline] PHST- 2022/02/11 00:00 [pmc-release] AID - 10.1186/s12943-022-01515-x [pii] AID - 1515 [pii] AID - 10.1186/s12943-022-01515-x [doi] PST - epublish SO - Mol Cancer. 2022 Feb 11;21(1):45. doi: 10.1186/s12943-022-01515-x.