Colorectal cancer-derived extracellular vesicles induce liver premetastatic immunosuppressive niche formation to promote tumor early liver metastasis

Dear Editor,To date,the effect of colorectal cancer(CRC)-derived extracellular vesicles(EVs)on liver pre-metastatic niche(PMN)remain incompletely understood.1 To investigate the role of CRC-derived EVs in the remodeling of the liver PMN,we isolated EVs from CT26 cell culture supernatant.The characteristics of EVs(the morphology,size,and markers)were identified by transmission electron microscopy(TEM),Nanoparticle Tracking Analysis(NTA),and western blotting(Supplementary Fig.S1a–e).Then,BALB/c mice with an intact liver immune status were pretreated with CRCderived EVs and phosphate-buffered saline(PBS)for one month,and a liver metastasis model was established via spleen injection of tumor cells to determine whether EVs influence liver metastasis(Fig.1a).Two hours after the operation,in vivo imaging indicated that the animal model was successfully established,and the tumor fluorescence intensity in the liver was consistent between the two groups(Supplementary Fig.S2a,b).Amazingly,the liver tumor fluorescence intensity in the EVs group was significantly stronger than that in the PBS group after 24 h(Fig.1b;Supplementary Fig.S2c,d).The number of liver tumor nodules in the EVs group was also significantly higher than that in the PBS group on day 4(Fig.1c;Supplementary Fig.S2e,f).

Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer

Antibody–drug conjugates(ADCs)take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells,which have become a powerful measure for cancer treatment in recent years.To develop a more effective therapy for human epidermal growth factor receptor 2(HER2)-positive cancer,we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1.The resulting ADCs,T-SA1–DM1 and T-SA2–DM1(drug-to-antibody ratio in the range of 3.2–3.5)displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro.In HER2-positive human ovarian cancer xenograft models,T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity.Importantly,three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1.On the basis of the analysis of luminescence imaging,anti-HER2 scFv–HSA fusion antibodies,especially T-SA1,showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab.Collectively,the novel type of ADCs is effective and selective targeting to HER2-positive cancer,and may be a promising antitumor drug candidate for further studies.