SIGLEC-3 (CD33) serves as an immune checkpoint receptor for HBV infection

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Abstract

Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant [KD]: 1.95 × 10–10 ± 0.21 × 10–10 M). Moreover, HBV activated SIGLEC-3 on myeloid cells and induced immunosuppression by stimulating immunoreceptor tyrosine-based inhibitory motif phosphorylation and SHP-1/-2 recruitment via α2,6-biantennary sialoglycans on HBsAg. An antagonistic anti–SIGLEC-3 mAb reversed this effect and enhanced cytokine production in response to TLR-7 agonist GS-9620 in PBMCs from CHB patients. Moreover, anti–SIGLEC-3 mAb alone was able to upregulate the expression of molecules involved in antigen presentation, such as CD80, CD86, CD40, MHC-I, MHC-II, and PD-L1 in CD14+ cells. Furthermore, SIGLEC-3 SNP rs12459419 C, which expressed a higher amount of SIGLEC-3, was associated with increased risk of hepatocellular carcinoma (HCC) in CHB patients (HR: 1.256, 95% CI: 1.027–1.535, P = 0.0266). Thus, blockade of SIGLEC-3 is a promising strategy to reactivate host immunity to HBV and lower the incidence of HCC in the CHB patient population.

Authors

Tsung-Yu Tsai, Ming-Ting Huang, Pei-Shan Sung, Cheng-Yuan Peng, Mi-Hua Tao, Hwai-I Yang, Wei-Chiao Chang, An-Suei Yang, Chung-Ming Yu, Ya-Ping Lin, Ching-Yu Bau, Chih-Jen Huang, Mei-Hung Pan, Chung-Yi Wu, Chwan-Deng Hsiao, Yi-Hung Yeh, Shiteng Duan, James C Paulson, Shie-Liang Hsieh