Oxygen microcapsules improve immune checkpoint blockade by ameliorating hypoxia condition in pancreatic ductal adenocarcinoma

Jiangchao Wu; Xun Wang; Li Chen; Jianing Wang; Junlei Zhang; Jianghui Tang; Yongtao Ji; Jinyuan Song; Lin Wang; Yaxing Zhao; Hui Zhang; Taohong Li; Jianpeng Sheng; Dong Chen; Qi Zhang; Tingbo Liang

doi:10.1016/j.bioactmat.2022.05.022

Oxygen microcapsules improve immune checkpoint blockade by ameliorating hypoxia condition in pancreatic ductal adenocarcinoma

Bioact Mater. 2022 Jun 2:20:259-270. doi: 10.1016/j.bioactmat.2022.05.022. eCollection 2023 Feb.

Authors

Jiangchao Wu^{1

2

3}, Xun Wang^{1

2

3}, Li Chen^{4

5}, Jianing Wang^{1

2

3}, Junlei Zhang^{1

2

3}, Jianghui Tang^{1

2

3}, Yongtao Ji^{1

2

3}, Jinyuan Song^{1

2

3}, Lin Wang^{1

2

3}, Yaxing Zhao^{1

2

3}, Hui Zhang^{1

2

3}, Taohong Li^{1

2

3}, Jianpeng Sheng^{1

2

3}, Dong Chen^{4

5}, Qi Zhang^{1

2

3}, Tingbo Liang^{1

2

3}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
² Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
³ Zhejiang University Cancer Center, Zhejiang University, Hangzhou, 310003, China.
⁴ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, #79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, China.
⁵ College of Energy Engineering and State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou, 310027, China.

Abstract

Rationale: Hypoxia in tumor microenvironment (TME) represents an obstacle to the efficacy of immunotherapy for pancreatic ductal adenocarcinoma (PDAC) through several aspects such as increasing the expression of immune checkpoints or promoting fibrosis. Reversing hypoxic TME is a potential strategy to improve the validity of immune checkpoint blockade (ICB).

Methods: Here, we synthesized polydopamine-nanoparticle-stabilized oxygen microcapsules with excellent stabilization, bioavailability, and biocompatibility for direct oxygen delivery into tumor sites by interfacial polymerization.

Results: We observed oxygen microcapsules enhanced the oxygen concentration in the hypoxia environment and maintained the oxygen concentration for a long period both in vitro and in vivo. We found that oxygen microcapsules could significantly improve the efficiency of ICB against PDAC in vivo. Mechanismly, combined treatments using oxygen microcapsules and ICB could reduce the infiltration of tumor-associated macrophages (TAMs) and polarized pro-tumor M2 macrophages into anti-tumor M1 macrophages. In addition, combined treatments could elevate the proportion of T helper subtype 1 cells (Th1 cells) and cytotoxic T lymphocytes cells (CTLs) to mediate anti-tumor immune response in TME.

Conclusion: In summary, this pre-clinical study indicated that reversing hypoxia in TME by using oxygen microcapsules was an effective strategy to improve the performances of ICB on PDAC, which holds great potential for treating PDAC in the future.

Keywords: Hypoxia; Oxygen microcapsules; PD-1; Pancreatic ductal adenocarcinoma; Tumor microenvironment.