A clinically acceptable strategy for sensitizing anti-PD-1 treatment by hypoxia relief

• Published in: Journal of controlled release 2021-07, Vol.335, p.408-419
• Main Authors: Jiang, Mengshi, Qin, Bing, Luo, Lihua, Li, Xiang, Shi, Yingying, Zhang, Junlei, Luo, Zhenyu, Zhu, Chunqi, Guan, Guannan, Du, Yongzhong, You, Jian
• Format: Article
• Language: English
• Subjects: Biosafety; Fluorocarbons; Hemoglobin; Oxygen delivery; PD-1 antibody
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.06.001

The hypoxic tumor microenvironment (TME) hinders the effectiveness of immunotherapy. Alleviating tumor hypoxia to improve the efficacy of immune checkpoint inhibitors (ICIs) represented by programmed cell death protein 1 (PD-1) antibody has become a meaningful strategy. In this study, we adopted three methods to alleviate hypoxia, including direct oxygen delivery using two different carriers and an indirect way involving HIF-1α inhibition. Both in vivo and in vitro experiments showed that liposomes modified with perfluorocarbon or hemoglobin (PFC@lipo or Hb@lipo) were able to efficiently load and release oxygen, relieving tumor hypoxia. However, the gas release behavior of PFC@lipo was uncontrollable, which might induce acute hyperoxia side effects during intravenous injection and reduce its biosafety. In contrast, whether administered locally or systemically, Hb@lipo revealed high animal tolerance, and was much safer than commercial HIF-1α inhibitor (PX-478), displaying prospects as a promising oxygen carrier for clinical practice. Pharmacodynamic experiments suggested that Hb@lipo helped PD-1 antibody break the therapeutic bottleneck and significantly inhibited the progression of 4 T1 breast cancer. But in CT26 colon cancer, the combination therapy failed to suppress tumor growth. After in-depth analysis and comparison, we found that the ratio of M1/M2 tumor associated macrophages (TAMs) between these two tumor models were dramatically different. And the lower M1/M2 ratio in CT26 tumors limited the anti-tumor effect of combination therapy. In this study, three methods for alleviating tumor hypoxia were compared from the perspectives of biosafety, efficacy and clinical applicability. Among them, Hb@lipo stood out, and its combined use with PD-1 antibody exhibit a distinct synergistic suppression effect on tumors with more M1 macrophages presented in the microenvironment. Our work provided a good reference for improving the efficacy of PD-1 antibody by alleviating tumor hypoxia. Hb@lipo could effectively load and deliver oxygen to the tumor site, relieve tumor hypoxia, and enhance the immunotherapy effect of PD-1 antibody (aPD1) on 4 T1 tumors, in which M1 macrophages were more than M2 macrophages. In contrast, the combination therapy had no therapeutic effect on CT26 tumors where M2 cells predominated in the microenvironment. [Display omitted] •Direct delivery of oxygen can relieve tumor hypoxia and sensitize anti-PD1 therapy.•More controlled oxygen relea