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Commentary
Open Access | 
10.1172/JCI189207
High IgG titers against EBV glycoprotein 42 correlate with lower risk of nasopharyngeal carcinoma
Benjamin E. Warner1,2 and Kathy H.Y. Shair1,3
1Cancer Virology Program, UPMC Hillman Cancer Center,
2Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, and
3Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Address correspondence to: Kathy H.Y. Shair, Hillman Cancer Center, 5117 Centre Avenue, Suite 1.8, Pittsburgh, Pennsylvania 15213, USA. Phone: 412.623.7717; Email: kas361@pitt.edu.
Find articles by Warner, B. in: JCI | PubMed | Google Scholar
1Cancer Virology Program, UPMC Hillman Cancer Center,
2Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, and
3Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Address correspondence to: Kathy H.Y. Shair, Hillman Cancer Center, 5117 Centre Avenue, Suite 1.8, Pittsburgh, Pennsylvania 15213, USA. Phone: 412.623.7717; Email: kas361@pitt.edu.
Find articles by Shair, K. in: JCI | PubMed | Google Scholar
Published February 17, 2025 - More info
J Clin Invest. 2025;135(4):e189207. https://doi.org/10.1172/JCI189207.
© 2025 Warner, et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
BACKGROUND EBV is associated with nasopharyngeal carcinoma (NPC), but the existence of a NPC protective antibody against EBV-associated antigens remains unclear.METHODS Patients with NPC and matched controls were identified from prospective cohorts comprising 75,481 participants in southern China. ELISA and conditional logistic regression were applied to assess the effects of gp42-IgG on NPC. The expression of HLA-II, the gp42 receptor, in nasopharyngeal atypical dysplasia and its effect on EBV infection of epithelial cells were evaluated.FINDINGS gp42-IgG titers were significantly lower in patients with NPC compared with controls across various follow-up years before NPC diagnosis (P < 0.05). Individuals in the highest quartile for gp42-IgG titers had a 71% NPC risk reduction compared with those in the lowest quartile (ORsQ4vsQ1= 0.29, 95% CIs = 0·15 to 0.55, P < 0.001). Each unit antibody titer increase was associated with a 34% lower risk of NPC (OR = 0.66, 95% CI = 0.54–0.81, Ptrend< 0.001). The protective effect of of gp42-IgG was observed in patients diagnosed 5 years or more, 1–5 years, and less than 1 year after blood collection (P < 0.05). HLA-II expression was detected in 13 of 27 specimens of nasopharyngeal atypical dysplasia, and its overexpression substantially promoted epithelial cell–origin EBV infection.CONCLUSION Elevated EBV gp42-IgG titers can reduce NPC risk, indicating that gp42 is a potential EBV prophylactic vaccine target.TRIAL REGISTRATION NCT00941538, NCT02501980, ChiCTR2000028776, ChiCTR2100041628.FUNDING Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0501003), National Natural Science Foundation of China (82030046, 82073625, 81860601, 82373655), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2019BT02Y198), and Central Financial Transfer Payment Projects of the Chinese Government, Cancer Research Grant of Zhongshan City.
Authors
Xiang-Wei Kong, Guo-Long Bu, Hua Chen, Yu-Hua Huang, Zhiwei Liu, Yin-Feng Kang, Yan-Cheng Li, Xia Yu, Biao-Hua Wu, Zi-Qian Li, Xin-Chun Chen, Shang-Hang Xie, Dong-Feng Lin, Tong Li, Shu-Mei Yan, Run-Kun Han, Nan Huang, Qian-Yu Wang, Yan Li, Ao Zhang, Qian Zhong, Xiao-Ming Huang, Weimin Ye, Ming-Fang Ji, Yong-Lin Cai, Su-Mei Cao, Mu-Sheng Zeng
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Antibody-based screening for nasopharyngeal carcinoma
EBV infection is closely associated with nasopharyngeal carcinoma (NPC) in endemic regions such as southern China (1). Screening populations for high-risk antibody signatures can reduce the burden of NPC by improving early diagnosis (2, 3). For example, mucosa-specific antibodies (IgA) against EBV proteins, such as EBNA1 and VCA viral capsid antigen (VCA) p18 and systemic antibodies (IgG) against BNLF2b can distinguish healthy individuals from those with early-stage NPC (2, 4, 5). Their utility in risk assessment has been likewise evaluated by profiling antibodies in healthy individuals who were later diagnosed with NPC (incident cases) (6–8). While such studies have revealed biomarkers of NPC risk, a protective antibody signature in healthy EBV carriers in NPC-endemic regions remains unclear. In this issue of the JCI, Kong et al. report that high levels of IgG against EBV glycoprotein 42 (gp42) were associated with reduced NPC risk across three independent prospective cohorts in southern China (Figure 1A) (9). Most adults are seropositive for EBV, but whether healthy carriers harbor serologic markers that correlate with a lower odds ratio for NPC is unknown. The authors quantified gp42-IgG by an ELISA coated with mammalian-expressed purified gp42 lacking the transmembrane region. Individuals with low gp42-IgG were at greater risk of NPC up to 5 years before diagnosis compared with healthy controls. This finding is intriguing because it suggests that neutralizing gp42-IgG may reduce the frequency of EBV infections in the nasopharynx and, by extension, the risk of developing NPC. Cytotoxic T lymphocyte (CTL) responses are important for the recognition of EBV antigens in NPC (10), but a role for humoral immunity in protection against cancer is as yet undefined. Emerging evidence from spatial transcriptomics have indicated that antibody-producing plasma cells are associated with antitumor apoptotic signatures (11).
Figure 1Elevated levels of gp42-IgG are associated with a reduced risk of NPC. (A) Serologic screen of incident NPC and matched healthy controls (1:3 ratio) from three independent prospective cohorts demonstrated individuals with higher titers of IgG against EBV gp42 (gp42-IgG) had a lower risk of NPC diagnosis. (B) Alternate replication in stratified epithelial cells and B cells produce virions that selectively target the reciprocal cell type. Kong and co-authors proposed that HLA-II primes the premalignant tissue for infection by three-part virions produced in the oral and nasal epithelium (9). In this model, abundant gp42-IgG could reduce the risk of EBV infection by interfering with membrane fusion.
Recent studies investigating neutralizing antibody levels and NPC risk have offered conflicting results (12–16). A previous case-control study by the same group using a smaller but different subset of plasma samples from the Sihui cohort (20 cases, 40 controls) did not show that gp42-IgG or -IgA levels correlated with NPC protection or neutralizing activity in B cell or epithelial cell lines (14). The 129 incident NPC cases and 387 controls across three cohorts in the present study is one of the largest prospective case-control studies to date (9, 17). The authors present in vitro and hisopathologic evidence that supports a proposed mechanism of gp42-IgG protection. Competition with soluble gp42 inhibited EBV infection of epithelial cells expressing HLA class II (HLA-II) (9). Indeed, a preclinical study showed that monoclonal antibodies targeting gp42 can directly inhibit HLA-II binding to neutralize B cell infection (18), but the in vivo relevance of neutralizing gp42 antibody and infection in the nasopharyngeal epithelium is unknown. A strong neutralizing antibody response can be detected during primary EBV infection and infectious mononucleosis (19), but cell-mediated immunity is thought to have a greater role in controlling disease associated with EBV reactivation (20, 21). Thus, exploring systems serology in the control of EBV infection prior to NPC development may confirm or reveal new targets for vaccine design. Current vaccine efforts are targeted at stimulating neutralizing antibodies against EBV surface antigens that will most likely reduce infection burden but may not be sterilizing. Whether these vaccines protect against cancer resulting from the outgrowth of a latent infection will necessitate the development of cancer models or observational studies from clinical trials (21).
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