1. School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China;
2. Department of Immunology, Institute of Basic Medical Science, Peking Union Medical College, Beijing 100730, China;
3. State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, China.
4. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
5. Tianjin Key Laboratory of Tumour Microenvironment and Neurovascular Regulation, Tianjin 300071, China.
6. Collaborative Innovation Center for Biotherapy, Nankai University, 94 Weijin Road, Tianjin 300071, China.
* Chunlei Guo and Yanan Chen contributed equally to this paper.
Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44+ breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2+ and CD206+ cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME.
Keywords: liposomal nanoparticles, anti-IL6R antibody, tumour microenvironment, metastasis, metastatic niche.