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J Cancer 2020; 11(3):648-656. doi:10.7150/jca.29705 This issue Cite

Research Paper

Increased Tim-3 expression on TILs during treatment with the Anchored GM-CSF vaccine and anti-PD-1 antibodies is inversely correlated with response in prostate cancer

Xinji Zhang^1*, Haixiong Chen^2*, Guanfeng Li^2*, Xiangyun Zhou², Yuqiang Shi¹, Feng Zou¹, Yuanxiang Chen¹, Jimin Gao³, Shaomin Yang^2✉, Shihao Wu^1✉, Zhaolin Long^1✉

1. Department of Urology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China;
2. Department of Radiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China;
3. Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
^*Those authors contributed equally.

✉ Corresponding authors: Zhaolin Long and Shihao Wu, 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; Email addresses: tanjieqiongedu.cn and urology12345com; Shaomin Yang, Department of Radiology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde District, Foshan), Foshan, 528300, China; Phone: +86 0757-22318611; fax: +86 0757-22318612; Email addresses: ysmsincom More

Abstract

Programmed death receptor-1 (PD-1) and T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) play important roles in tumor immune evasion. PD-1 blockade could produce an effective antitumor effect in many solid tumors except prostate cancer (PCa) because of rare programmed death ligand-1 (PD-L1) expression on PCa cells. Streptavidin (SA)-GM-CSF surface-anchored tumor cell (Anchored GM-CSF) vaccines could increase the number of tumor-infiltrating lymphocytes (TILs) and induce specific antitumor immune responses. The Anchored-GM-CSF vaccine and anti-PD-1 antibodies exerted synergistic effects in mouse models of PCa metastasis. However, the response rate was low due to the presence of other negative regulatory pathways. Tim-3 expression could be upregulated at resistance to combination therapy with anti-PD-1 antibodies and the Anchored GM-CSF vaccine. Sequential administration of anti-PD-1 and anti-Tim-3 antibodies could further improve the efficacy of the Anchored GM-CSF vaccine therapy, and tumor regression was noted in over 60% of animals. This triple therapy improved the specific cytotoxic activity, proliferation and secretion of CD8⁺ TILs and reduced the production of tumor-promoting cytokines. These findings indicated that this triple therapy could induce a robust antitumor immune response in mouse models of PCa.

Keywords: programmed death receptor-1, T cell immunoglobulin and mucin domain-containing protein-3, prostate cancer, vaccine, immunotherapy.

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