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J Cancer 2021; 12(7):2000-2009. doi:10.7150/jca.44769 This issue Cite

Research Paper

Sequential administration of anti-PD-1 and anti-Tim-3 combined with an SA-GM-CSF-anchored vaccine overcomes adaptive immune resistance to reject established bladder cancer

Xinji Zhang^1,2#, Guang Liu^2#, Xianghua Shi^3#, Xiaojun Shi¹, Jinlong Li⁴, Lijun Mo⁴, Jimin Gao⁵, Zhaolin Long^2✉#, Wanlong Tan^1✉#

1. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
2. Department of Urology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China.
3. Department of Urology, The First People's Hospital of Foshan, Guangdong,528000, China.
4. Institute of Biotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
5. Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Wanlong Tan, Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Phone: +86 020-61641762; fax: +86 020-61641763; E-mail: yaomj5sysu.edu.cn. Zhaolin Long, Department of Urology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China; Phone: +86 0757-22318701; fax: +86 0757-22318702; E-mail: urology12345com. More

Abstract

Program death receptor-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play an important role in tumor immune evasion. PD-1 blockade could produce an effective anti-tumor effect but the response rate was low due to lacking of tumor infiltrating lymphocytes (TILs) and existing of other negative regulatory pathways. Streptavidin(SA)-GM-CSF surface-anchored tumor cells vaccine could induce specific anti-tumor immune response. However, this vaccine failed to induce regression of established tumor because it also up-regulated PD-1 expression on tumor cells dependent on IFNγ and up-regulated PD-1/Tim-3 expression on CD8⁺ TILs. Subsets of CD8⁺ TILs assay showed that PD-1 expression was closely associated with CD8⁺ TILs exhaustion, and Tim-3 expression was closely correlated with secretion function but not proliferation of CD8⁺ TILs. Sequential administration of anti-PD-1 and anti-Tim-3 could further improve the efficacy of SA-GM-CSF-anchored vaccine therapy, and tumor regression was noted in over 50%. This triple therapy improves the specific cytotoxic activity and decreased the apoptosis of CD8⁺ TILs. These findings indicated that this triple therapy could induce a more robust anti-tumor immune response.

Keywords: program death receptor 1, T cell immunoglobulin and mucin domain-containing protein-3, bladder cancer, vaccine, immunotherapy

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