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

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 Zhang1*, Haixiong Chen2*, Guanfeng Li2*, Xiangyun Zhou2, Yuqiang Shi1, Feng Zou1, Yuanxiang Chen1, Jimin Gao3, Shaomin Yang2✉, Shihao Wu1✉, Zhaolin Long1✉

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.

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Citation:
Zhang X, Chen H, Li G, Zhou X, Shi Y, Zou F, Chen Y, Gao J, Yang S, Wu S, Long Z. 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. J Cancer 2020; 11(3):648-656. doi:10.7150/jca.29705. Available from http://www.jcancer.org/v11p0648.htm

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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.