2. Academic Validation
  3. Inhibitor of glutamine metabolism V9302 promotes ROS-induced autophagic degradation of B7H3 to enhance antitumor immunity

Inhibitor of glutamine metabolism V9302 promotes ROS-induced autophagic degradation of B7H3 to enhance antitumor immunity

  • J Biol Chem. 2022 Apr;298(4):101753. doi: 10.1016/j.jbc.2022.101753.
Qian Li 1,  Xiaofang Zhong 1,  Weicheng Yao 2,  Junli Yu 1,  Chao Wang 3,  Zongyan Li 4,  Shengqing Lai 1,  Fanli Qu 1,  Xiaoyan Fu 1,  Xiaojia Huang 1,  Dawei Zhang 5,  Yujie Liu 6,  Haiyan Li 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Breast Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 5 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: zhangdaweiwinner@163.com.
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: liuyujie554@163.com.
  • 7 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Department of Breast Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: lihy27@mail.sysu.edu.cn.
PMID: 35189139 DOI: 10.1016/j.jbc.2022.101753
Abstract

Despite the enormous successes of anti-PD-1/PD-L1 immunotherapy in multiple other Cancer types, the overall response rates of breast Cancer remain suboptimal. Therefore, exploring additional immune checkpoint molecules for potential Cancer treatment is crucial. B7H3, a T-cell coinhibitory molecule, is specifically overexpressed in breast Cancer compared with normal breast tissue and benign lesions, making it an attractive therapeutic target. However, the mechanism by which B7H3 contributes to the Cancer phenotype is unclear. Here we show that the expression of B7H3 is negatively related to the number of CD8+ T cells in breast tumor sites. In addition, analysis of the differentially expressed B7H3 reveals that it is inversely correlated to autophagic flux both in breast Cancer cell lines and clinical tumor tissues. Furthermore, block of Autophagy by bafilomycin A1 (Baf A1) increases B7H3 levels and attenuates CD8+ T cell activation, while promotion of Autophagy by V9302, a small-molecule inhibitor of glutamine metabolism, decreases B7H3 expression and enhances granzyme B (GzB) production of CD8+ T cells via regulation of Reactive Oxygen Species (ROS) accumulation. We demonstrate that combined treatment with V9302 and anti-PD-1 monoclonal antibody (mAb) enhances antitumor immunity in syngeneic mouse models. Collectively, our findings unveil the beneficial effect of V9302 in boosting antitumor immune response in breast Cancer and illustrate that anti-PD-1 together with V9302 treatment may provide synergistic effects in the treatment of patients insensitive to anti-PD-1 therapy.

Keywords

B7H3; CTLs activation; V9302; anti-PD-1 immunotherapy; autophagy.

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