Human/mouse CD137 agonist, JNU-0921, effectively shrinks tumors through enhancing the cytotoxicity of CD8 <sup>+</sup> T cells in cis and in trans-Reference-Cited by-同舟云学术

Human/mouse CD137 agonist, JNU-0921, effectively shrinks tumors through enhancing the cytotoxicity of CD8 ⁺ T cells in cis and in trans

Published:2024-08-23 Issue:34 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Liu Lu¹^ORCID,Chen Fenghua¹^ORCID,Li Shan²^ORCID,Yang Tong¹^ORCID,Chen Shuzhen¹^ORCID,Zhou Yang³^ORCID,Lin Zejian¹^ORCID,Zeng Guandi¹^ORCID,Feng Pengju⁴^ORCID,Shu Hong-Bing⁵^ORCID,Zhou Qian¹^ORCID,Ding Ke³^ORCID,Chen Liang¹^ORCID

Affiliation:

1. Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.

2. Hangzhou Institute of Medicine Chinese Academy of Sciences, Hangzhou 310018 Zhejiang, China.

3. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, Guangzhou 510632, China.

4. Department of Chemistry, College of Chemistry and Materials Science, Jinan University Guangzhou, Guangzhou 510632, China.

5. Medical Research Institute, Wuhan University, Wuhan 430071, China.

Abstract

Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8 + T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adp8647

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