Gene delivery of TIPE2 inhibits breast cancer development and metastasis via CD8+T and NK cell-mediated antitumor responses.
Breast cancer is the second leading cause of cancer-related deaths in the female patients which was mainly caused by metastasis. Development of target gene therapy for breast cancer to suppress tumor progress and metastasis will improve the therapeutic options and be of great benefit to the patients. Tumor necrosis factor-alpha-induced protein 8-like 2 is a novel molecule for maintaining immune homeostasis and is involved in cancer development. In the present study, we overexpressed TIPE2 in breast cancer cells to investigate the role of TIPE2 in the development of breast cancer. Our results showed that overexpression of TIPE2 significantly inhibited the proliferation of 4T1 cells in vitro and in vivo. We constructed a non-viral targeted gene therapeutic system by using the minicircle plasmids expressing TIPE2. We found that the growth and metastasis of breast cancer was significantly inhibited by hydrodynamic gene delivery of TIPE2 plasmids in vivo. Mechanistically, TIPE2 increased T and NK cells, and decreased MDSCs. Gene delivery of TIPE2 up-regulated the production of IFN-γ and TNF-α by CD8+T and NK cells in spleens and tumor microenvironment, and enhanced the cytotoxic activity of CD8+T and NK cells. Taken together, TIPE2 inhibited breast cancer development and metastasis possibly via promoting CD8+T and NK cell-mediated antitumor immune responses. Thus, the results indicate that TIPE2 may be a potential therapeutic target for breast cancer therapy.
School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China; State Institute of Pharmaceutical Industry, Shanghai 201203, People's Republic of China.
Zhenhua
Z
Zhang
State Institute of Pharmaceutical Industry, Shanghai 201203, People's Republic of China.
Li
L
Liu
State Institute of Pharmaceutical Industry, Shanghai 201203, People's Republic of China.
Shousong
S
Cao
School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China. Electronic address: zhuyizhun2016@163.com.
Yizhun
Y
Zhu
State Institute of Pharmaceutical Industry, Shanghai 201203, People's Republic of China. Electronic address: meiqibing2016@163.com.
Qibing
Q
Mei
D000818:Animals; D041702:BALB 3T3 Cells; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
D047908:Intracellular Signaling Peptides and Proteins; C529002:TIPE2 protein, mouse
Breast cancer; Gene delivery; Lung metastasis; TIPE2