Noninvasively Deciphering the Immunosuppressive Tumor Microenvironment Using Galectin-1 PET to Inform Immunotherapy Responses

作者：Ning Liu, Xiujie Yang, Chao Gao, Jianze Wang, Yuwen Zeng, Linyu Zhang, Qi Yin, Ting Zhang, Haoyi Zhou, Kui Li, Jinhong Du, Shixin Zhou, Xuyang Zhao, Hua Zhu, Zhi‐gang Yang, Zhaofei Liu · 发表于：Journal of Nuclear Medicine · 年份：2024 · DOI：10.2967/jnumed.123.266888 · 被引用次数：10 · 研究领域：Galectins and Cancer Biology、Glycosylation and Glycoproteins Research、Cancer Mechanisms and Therapy

Immune checkpoint blockade (ICB) has achieved groundbreaking results in clinical cancer therapy; however, only a subset of patients experience durable benefits. The aim of this study was to explore strategies for predicting tumor responses to optimize the intervention approach using ICB therapy. Methods: We used a bilateral mouse model for proteomics analysis to identify new imaging biomarkers for tumor responses to ICB therapy. A PET radiotracer was synthesized by radiolabeling the identified biomarker-targeting antibody with 124 I. The radiotracer was then tested for PET prediction of tumor responses to ICB therapy. Results: We identified galectin-1 (Gal-1), a member of the carbohydrate-binding lectin family, as a potential negative biomarker for ICB efficacy. We established that Gal-1 inhibition promotes a sensitive immune phenotype within the tumor microenvironment (TME) for ICB therapy. To assess the pre-ICB treatment status of the TME, a Gal-1–targeted PET radiotracer, 124 I-αGal-1, was developed. PET imaging with 124 I-αGal-1 showed the pretreatment immunosuppressive status of the TME before the initiation of therapy, thus enabling the prediction of ICB resistance in advance. Moreover, the use of hydrogel scaffolds loaded with a Gal-1 inhibitor, thiodigalactoside, demonstrated that a single dose of thiodigalactoside–hydrogel significantly potentiated ICB and adoptive cell transfer immunotherapies by remodeling the immunosuppressive TME. Conclusion: Our study u...