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Background
Human leukocyte antigen (HLA)-G has multiple isoforms with unique molecular structures and receptor-binding specificities. Different HLA-G isoform(s) may have distinct clinical relevance. Because of 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 retrospectively in 345 patients with colorectal cancer (CRC).
Results
The expression rate of HLA-G2/6 (90/345, 26.1%) was significantly lower than that of HLA-G1/4/5 (275/345, 79.7%; p < 0.001). Patients with HLA-G2/6 expression had significantly 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). Multivariate Cox proportional-hazard model results indicated that HLA-G2/6 was an independent prognostic factor for CRC (hazard ratio [HR] = 1.530, 95% CI: 1.125–2.081; p = 0.007). Moreover, HLA-G2/6 expression showed stratified prognostic significance among several CRC patient subgroups, specifically in female patients (p = 0.003), younger patients (<66 years p < 0.001), patients with colon cancer ( p = 0.045), those at stage pT3 ( p = 0.008), pN1 ( p = 0.020), p M0 ( p = 0.009), and AJCC stage III ( p = 0.005). However, no statistical significance was found between HLA-G1/4/5 isoform expression and patient prognosis in CRC.
Conclusions
This is the first study to generate mAbs for the HLA-G2/6 and HLA-G1/4/5 isoforms. Our findings reveal 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 suggests that HLA-G isoform typing may be necessary for HLA-G-targeted cancer immunotherapy.
Details
Metastasis;
Precision medicine;
Immunotherapy;
Cancer therapies;
Leukocytes;
Isoforms;
Ethics;
Peptides;
Colorectal cancer;
Colon cancer;
Clinical significance;
Cancer immunotherapy;
Laboratory animals;
Patients;
Tissue typing;
Medical prognosis;
Cloning;
Histocompatibility antigen HLA;
Immune response;
Immunohistochemistry;
Hospitals;
Committees;
Colorectal carcinoma;
Antigens
1 Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China, Key Laboratory of Human Leukocyte antigen - G (HLA-G) Research & Development of Taizhou, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
2 Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
3 Department of Urology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
4 Key Laboratory of Human Leukocyte antigen - G (HLA-G) Research & Development of Taizhou, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China, Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China, Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
5 Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China, Key Laboratory of Human Leukocyte antigen - G (HLA-G) Research & Development of Taizhou, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China, Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China