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Theranostics 2023; 13(14):4836-4857. doi:10.7150/thno.86792 This issue Cite

Research Paper

Blocking Tim-3 enhances the anti-tumor immunity of STING agonist ADU-S100 by unleashing CD4⁺ T cells through regulating type 2 conventional dendritic cells

Jing Luo^1,2,3,4#, Shuju Pang^1,2,3,4#, Zhenzhen Hui^1,2,3,5, Hua Zhao^1,2,3,4,7, Shilei Xu^1,2,3,6, Wenwen Yu^1,2,3,4, Lili Yang^1,2,3,4, Qian Sun^1,2,3,4,7, Xishan Hao⁷, Feng Wei^1,2,3,4,7✉, Jian Wang^1,2,3,4✉, Xiubao Ren^{1,2,3,4,5,7✉}

1. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, China.
2. Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
3. Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, 300060, China.
4. Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
5. Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
6. Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
7. Haihe Laboratory of Cell Ecosystem, Tianjin 300060, China.
# These authors contributed equally to this work: Jing Luo and Shuju Pang.

✉ Corresponding authors: Xiubao Ren, Jian Wang, Feng Wei. E-mail: renxiubaocom; Wangjian112358com; fengwei03edu.cn. Tel: +86-022-2353-7796; Fax: +86-022-2353-7796.

Abstract

Rationale: An immunosuppressive tumor microenvironment (TME) is a major obstacle in tumor immunotherapy. Stimulator of interferon genes (STING) agonists trigger an inflammatory innate immune response to potentially overcome tumor immunosuppression. While STING agonists may hold promise as potential cancer therapy agents, tumor resistance to STING monotherapy has emerged in clinical trials, and the mechanisms remain unclear.

Methods: The in vivo anti-tumor immunity of STING agonist ADU-S100 (S100), plus anti-T cell immunoglobulin and mucin-domain containing-3 antibody (αTim-3) were measured using murine tumor models. Tumor-specific T cell activation and alterations in the TME were detected using flow cytometry. The maturation and function of dendritic cells (DC) were also measured using flow cytometry, and the importance of CD4⁺ T cells in combination therapy was measured by blocking antibodies. Additionally, the effect of S100 on CD4⁺ T was verified via in vitro assays. Lastly, the impact of conventional dendritic cells (cDC) 2 with a high expression of Tim-3 on survival or therapeutic outcomes was further evaluated in human tumor samples.

Results: S100 boosted CD8⁺ T by activating cDC1 but failed to initiate cDC2. Mechanistically, the administration of S100 results in an upregulation of Tim-3 expressed in cDC2 (Tim-3⁺cDC2) in both mice and humans, which is immunosuppressive. Tim-3⁺cDC2 restrained CD4⁺ T and attenuated the CD4⁺ T-driven anti-tumor response. Combining S100 with αTim-3 effectively promoted cDC2 maturation and antigen presentation, releasing CD4⁺ T cells, thus reducing tumor burden while prolonging survival. Furthermore, high percentages of Tim-3⁺cDC2 in the human TME predicted poor prognosis, whereas the abundance of Tim-3⁺cDC2 may act as a biomarker for CD4⁺ T quality and a contributing indicator for responsiveness to immunotherapy.

Conclusion: This research demonstrated that blocking Tim-3 could enhance the anti-tumor immunity of STING agonist ADU-S100 by releasing CD4⁺ T cells through regulating cDC2. It also revealed an intrinsic barrier to ADU-S100 monotherapy, besides providing a combinatorial strategy for overcoming immunosuppression in tumors.

Keywords: STING, ADU-S100, Tim-3, DC, Cancer immunotherapy

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