Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma

Cai, Yiqing; Chen, Xiaomin; Lu, Tiange; Fang, Xiaosheng; Ding, Mengfei; Yu, Zhuoya; Hu, Shunfeng; Liu, Jiarui; Zhou, Xiangxiang; Wang, Xin

doi:10.7150/ijbs.85236

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Int J Biol Sci 2023; 19(14):4627-4643. doi:10.7150/ijbs.85236 This issue Cite

Research Paper

Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma

Yiqing Cai¹, Xiaomin Chen¹, Tiange Lu¹, Xiaosheng Fang^2,3,4,5, Mengfei Ding¹, Zhuoya Yu¹, Shunfeng Hu¹, Jiarui Liu¹, Xiangxiang Zhou^2,3,4,5✉, Xin Wang^1,2,3,4,5✉

1. Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China.
2. Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
3. Shandong Provincial Engineering Research Center of Lymphoma, Jinan, Shandong, 250021, China.
4. Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, 250021, China.
5. National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 251006, China.

✉ Corresponding authors: Xin Wang, M.D., Ph.D. Director & Professor, Department of Hematology, Shandong Provincial Hospital, Shandong University, No.324, Jingwu Road, Jinan, Shandong 250021, China; Tel: 0086-531-68776358 (B); 0086-13156012606 (M); More

Citation:

Cai Y, Chen X, Lu T, Fang X, Ding M, Yu Z, Hu S, Liu J, Zhou X, Wang X. Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma. Int J Biol Sci 2023; 19(14):4627-4643. doi:10.7150/ijbs.85236. https://www.ijbs.com/v19p4627.htm

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Abstract

Genomic instability is a significant driver of cancer. As the sensor of cytosolic DNA, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in regulating anti-tumor immunity and cell death. However, the role and regulatory mechanisms of STING in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we reported that sterile alpha motif and HD domain-containing protein 1 (SAMHD1) deficiency induced STING expression and inhibited tumor growth in DLBCL. High level of SAMHD1 was associated with poor prognosis in DLBCL patients. Down-regulation of SAMHD1 inhibited DLBCL cell proliferation both in vitro and in vivo. Moreover, we found that SAMHD1 deficiency induced DNA damage and promoted the expression of DNA damage adaptor STING. STING overexpression promoted the formation of Caspase 8/RIPK3/ASC, further leading to MLKL phosphorylation, Caspase 3 cleavage, and GSDME cleavage. Up-regulation of necroptotic, apoptotic, and pyroptotic effectors indicated STING-mediated PANoptosis. Finally, we demonstrated that the STING agonist, DMXAA, enhanced the efficacy of a PD-L1 inhibitor in DLBCL. Our findings highlight the important role of STING-mediated PANoptosis in restricting DLBCL progression and provide a potential strategy for enhancing the efficacy of immune checkpoint inhibitor agents in DLBCL.

Keywords: DLBCL, SAMHD1, STING, PANoptosis, DMXAA.

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APA

Cai, Y., Chen, X., Lu, T., Fang, X., Ding, M., Yu, Z., Hu, S., Liu, J., Zhou, X., Wang, X. (2023). Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma. International Journal of Biological Sciences, 19(14), 4627-4643. https://doi.org/10.7150/ijbs.85236.

ACS

Cai, Y.; Chen, X.; Lu, T.; Fang, X.; Ding, M.; Yu, Z.; Hu, S.; Liu, J.; Zhou, X.; Wang, X. Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma. Int. J. Biol. Sci. 2023, 19 (14), 4627-4643. DOI: 10.7150/ijbs.85236.

NLM

CSE

Cai Y, Chen X, Lu T, Fang X, Ding M, Yu Z, Hu S, Liu J, Zhou X, Wang X. 2023. Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma. Int J Biol Sci. 19(14):4627-4643.

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