ORIGINAL RESEARCH article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1672144
This article is part of the Research TopicHLA-G in Health and Disease: Comprehensive Insights and Future Therapeutic DirectionsView all 3 articles
Human leukocyte antigen-G isoform HLA-G2/6, but not HLA-G1/4/5, is an independent indicator of poor survival in patients with colorectal cancer
Provisionally accepted
- Taizhou Hospital, Wenzhou Medical University, Linhai, China
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Background: Human leukocyte antigen (HLA)-G has multiple isoforms with unique molecular structure and receptor binding specificity. Different HLA-G isoforms(s) could have different clinical relevance. Due to the lack of isoform-specific monoclonal antibodies (mAbs), the clinical significance of HLA-G isoforms (HLA-G1 to HLA-G7), except HLA-G1 and HLA-G5, remains largely unknown. Methods: In this study, mAbs against HLA-G2/6 and HLA-G1/4/5 isoforms were generated and characterized. Expression of HLA-G2/6 and HLA-G1/4/5 isoforms was analyzed by immunohistochemistry, and clinical significance was evaluated in 345 patients with colorectal cancer (CRC) retrospectively. Results: The expression rate of HLA-G2/6 (90/345, 26.1%) was remarkably lower than that of the HLA-G1/4/5 (275/345, 79.7%; p<0.001). Patients with HLA-G2/6 expression was significantly associated with poorer overall survival (OS) [median OS: 6.3 years (95% CI: 4.1 ~8.5) vs. 10.0 years (95% CI: 7.6 ~12.4); p=0.008], and multivariate Cox proportional hazard model results showed that HLA-G2/6 was an independent prognostic factor for CRC [hazard ratios (HR) =1.530, (95% CI: 1.125 ~2.081); p=0.007). Moreover, HLA-G2/6 expression showed stratified prognostic significance among the following CRC patient subgroups, specifically in female patients (p=0.003), younger patients (p<0.001), patients with colon cancer (p=0.045), patients at stage pT3 (p=0.008), pN1 (p=0.020), pM0 (p=0.009) and AJCC III (p=0.005). However, no statistical significance was found for HLA-G1/4/5 isoform expression to the prognosis of patients with CRC. Conclusions: This is the first study to generate mAbs for the HLA-G2/6 and HLA-G1/4/5 isoforms. Our findings revealed that HLA-G2/6, but not HLA-G1/4/5 expression, is an independent prognostic indicator for patients with CRC. In the context of precision medicine, our study also indicates that it is necessary to perform HLA-G isoform-typing for HLA-G targeted cancer immunotherapy.
Keywords: HLA-G, isoforms, Monoclonal antibody, colorectal cancer, prognosis
Received: 24 Jul 2025; Accepted: 03 Oct 2025.
Copyright: © 2025 Zhang, Han, Zhang, Lin, Yan and Lin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei-Hua Yan, yanwh@enzemed.com
Aifen Lin, linaf@enzemed.com
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